CZ2001722A3 - Azabicyclic compounds for modulating inhibition of cell adhesion, pharmaceutical preparations and use - Google Patents

Abstract

Aza-bicyclic compounds of formula (I) wherein R 1 is R3-Z3-, R3-L2-R4-Z3-, R3-L3-Ar'-L4-Z3-, or R3-L3- Ar'-L2-R4-Z3-, R2 is hydrogen, halogen, lower alkyl or lower alkoxy; A1 means a straight chain alkylene group containing 1 to 3 carbon atoms optionally substituted by one or more multiple groups selected from the group consisting of alkyl arylalkyl; , heteroaryl, heteroarylalkyl, imino, oxo, thioxo, or alkyl a group substituted with -ZR6, -ΝΥ'2, -CO2R6 or -C (= O) - NY * Y2; L1 represents a direct bond, an alkenylene group, alkylene, alkynylene, cycloalkenylene, cycloalkylene, heteroaryldiyl, heterocycloalkylene or an arylene group, each of which is optionally substituted; Y is carboxy or bioisoster and the corresponding N-oxides and their drug precursors, a pharmaceutically acceptable salts and solvates (such as hydrates) these compounds and their N-oxides and prodrugs. The thio compounds have valuable pharmaceutical properties, in particular the ability to regulate the interaction of VCAM-1 and fibronectin with intergrin VLA-4 (a4bl).

Description

Aza-bicyclic compounds that modulate cell adhesion inhibition, intermediates, pharmaceutical compositions containing these compounds, and uses of these compounds

Field of the invention

The invention relates to aza-bicyclic compounds, to a process for their preparation, to intermediates thereof, to pharmaceutical compositions containing them, and to the use of these compounds in the treatment of diseases which can be modulated by inhibiting cell adhesion.

BACKGROUND OF THE INVENTION

Cell adhesion is the process by which cells connect to each other, migrate to a specific target, or settle in extracellular matter. Many cell-cell and cell-extracellular matrix interactions are mediated by protein ligands (eg fibronectin, VCAM-1 and vitronectin) and their integrin receptors (eg. Α5β1 (VLA-5), α4β1 (VLA-4) and ανβ3). Recent studies have shown that these interactions play an important role in many physiological (such as embryo development and wound healing) and pathological conditions (such as tumor cell invasion and metastasis, inflammation, atherosclerosis, and autoimmune diseases).

Many proteins serve as ligands for integrin receptors. In general, proteins recognized by integrins fall into one of three groups: extracellular matter proteins, plasma proteins, and cell surface proteins. Extracellular matrix proteins such as collagen, fibronectin, fibrinogen, laminin, thrombospondin and vitronectin bind to a variety of integrins. Many of these adhesive proteins also circulate in plasma and bind to activated blood cells. Other plasma components that are integrin ligands include fibrinogen and factor X. Cell-bound ligands for certain integrins also include cell-bound C3bi complement and certain transmembrane proteins, such as an Ig-like cell adhesion molecule (ICAM-1,2, 3) and a vascular cell adhesion molecule (VCAM-1), which are members of the parent Ig family.

Integrins are heterodimeric cell surface receptors that consist of two subunits called α and β. There are at least fifteen different α subunits (α1-α9, α-L, α-M, α-X, α-IIb, α-V and α-E) and at least seven distinct β (β1-β7) subunits. The integrin family may be further subdivided into groups based on β subunits, which may be associated with one or more α subunits. The most widespread integrins belonging to the β family are also known as very late antigens (VLAs). The second group of integrins are leukocyte-specific receptors and consist of one of three α-L, α-M or α-X subunits complexed to the β2 protein. The third group of integrins are α-ΙΙύβ3 and α ~ νβ3 cytoadhesins.

In principle, the present invention relates to compositions that modulate the interaction of VCAM-1 ligand with its α4β1 integrin receptor (VLA-4), which is expressed on a number of hemopoietic cells and stable cell lines, including hemopoietic precursors, peripheral and cytotoxic T lymphocytes, B lymphocytes , monocytes, thymocytes and eosinophils.

Integrin α4β1 mediates both types of cell-cell and cell-extracellular matter interactions. Cells expressing α4β1 bind the carboxy-terminal cell binding domain (CS-1)

• e ···· 9 9 9

99999 9999999 8 9

The extracellular mass of fibronectin, the cytokine-inducible surface protein of the endothelial cell VCAM-1 and to each other, thereby stimulating homotypic aggregation. VCAM-1 expression by endothelial cells is activated by pro-inflammatory cytokines such as INF-gamma, TNF-alpha, IL-1beta and IL-4.

Regulation of α4β1-mediated cellular adhesion is important in a number of physiological processes, including T cell proliferation, germ cell localization of B cells, and adhesion of activated T cells and eosinophils to endothelial cells. Evidence for the involvement of VLA-4 / VCAM-1 interactions in various disease processes such as melanoma cell division in metastases, synovial membrane infiltration by T lymphocytes in rheumatoid arthritis, autoimmune diabetes, colitis and leukocyte penetration of the blood-brain barrier in experimental autoimmune encephalomyelitis peripheral blood vessels, cardiovascular disease, and multiple sclerosis, have been accumulated in investigating the role of CS-1 (a fibronectin variable region to which α4β1 binds via the Leu-Asp-Val sequence), and VLA-4 or VCAM-1 specific antibodies on various in vitro and in vivo experimental models of inflammation. For example, in an experimental model of streptococcal cell wall arthritis in a rat, intravenous administration of CS-1 at the onset of arthritis suppressed both acute and chronic inflammation (Wahl,

S. Μ. , et al., J. Clin. Invest., 1994, 94, 655-662).

In the oxazalone-induced inflammation model (contact hypersensitivity reaction) in mice, intravenous administration of anti-α4 specific monoclonal antibodies significantly inhibited (50-60% reduction in ear swelling) efferent response (Chisholm, PL et al., J. Immunol., 23, 682-688 (1993). In the model

allergic bronchoconstriction in sheep blocked the HP1 / 2, arrti-a4 monoclonal antibody, administered intravenously or aerosol, late response and development of airway hypersensitivity (Abraham, W. Μ., et al., J. Clin. Invest.,

93, 776-787, 1994).

A new class of aza-bicyclic compounds having valuable pharmaceutical properties, in particular the ability to regulate the interaction of VCAM-1 and fibronectin with integrin VLA-4 (α4β1) has been found.

SUMMARY OF THE INVENTION

One aspect of the present invention are aza-bicyclic compounds of formula (I):

in which:

represents a group selected from the group consisting of (i) R ³ -Z ³ (ii) R ³ -L ² -R ⁴ -Z ³ (iii) R ³ -L ³ -Ar ¹ -L ⁴ -Z ³ -, and ( iv) R ³ -L ³ -Ar ¹ -L ² -R ⁴ -Z ³ -,

R is hydrogen, halogen, lower alkyl or lower alkoxy;

represents alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkinyl, cycloalkenyl, cycloalkenyl, heteroarylalenyl, heteroarylalenynyl, a heterocycloalkyl group or a heterocycloalkylalkyl group;

R ⁴ represents an alkylene group, an alkenylene group or an alkynylene group;

r5 represents a hydrogen atom or a lower alkyl group;

r6 is hydrogen, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl or heteroarylalkyl;

and R 6 ^and each independently represent a hydrogen atom or a lower alkyl group;

r8 is hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;

R 6 represents an alkyl group, an aryl group, a cycloalkyl group, a heteroaryl group or a 4-functional heterocycloalkyl group or an alkyl-substituted aryl group, an acidic group , cycloalkyl, heteroaryl, heterocycloalkyl, -S (O) _m R ³ , -C (= O) -NY ⁴ Y ³ or -NY ⁴ Y ⁵ ;

® R ¹ is hydrogen, R ³ or alkyl substituted with alkoxy, cycloalkyl, hydroxy, mercapto, alkylthio or -NY ⁴ Y ^5;

rH and R ³ · ³ independently of each other are selected from the group consisting of hydrogen and amino acid side chain forming groups, acidic functional groups, R ³ , -C (= O) -R ³ , or -C (= O) - NY ⁴ Y ⁵ , or an alkyl group substituted with an acidic functional group, R ³ , -NY ⁴ Y ³ , -NH-C (= O) -R ³ , -C (= O) -R ⁴ -NH 2, -C 1-4 - aP-NH 3, -C (= O) -R ⁴ -CO ² H or -C (= O) -NY ⁴ Y ⁵ ;

or R ³ · ® and R 4 or R 4 -θ and R 4 together with the atoms to which they are attached form a three to six membered heterocycloalkyl ring,

R (2) represents an alkylene group having 1 to 6 carbon atoms optionally substituted by R;

R ⁴ represents an alkyl group, an aryl group, an arylalkyl group, a cycloalkyl group, a cycloalkylalkyl group, a heteroaryl group, a heteroarylalkyl group, a heterocycloalkyl group or a heterocycloalkylalkyl group;

A 1 represents a straight chain alkylene group having 1 to 3 carbon atoms optionally substituted by one or more groups selected from the group consisting of alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, amino, oxo, thioxo, or alkyl a group substituted with -ZR ⁵ , -NY ¹ Y ² , -CO ₂ R ⁶ or -C (= O) -NY ¹ Y ² ;

Ar * represents an arylene group or a heteroaryldiyl group;

L is (i) a direct bond, (ii) an alkenylene group, an alkylene group, an alkynylene group, a cycloalkenylene group, a cycloalkylene group, a heteroaryldiyl group, a heterocycloalkylene group or an arylene group, each optionally substituted by an acidic functional group, cyano group , oxo, -S (O) _m R ⁹ , R ⁵ , -C (= O) -R ⁵ , -C (= O) -OR ⁵ , -N (R ⁸ ) -C (= O) -R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ² R ⁹ , -NY ⁴ Y ⁵ or - [C (= O) -N (R ¹⁰ ) -C (R ⁸ ) ⁵ ) (R ¹¹ )] p C (= O) -NY ⁴ Y ⁵ , or (b) an alkyl group substituted with an acidic functional group or -S (O) _r R ⁹ , -C (= O) -NY ⁴ Y ⁵ or -NY ⁴ Y ⁵ ;

(iii) a - [C (= 0) -N (R ¹⁰⁾ -C (R ⁵⁾ (R ^11)] _p - connection, (iv) a -Z ² -R ¹² - connection;

(v) -C (= O) -CH ₂ -C (= O) - linkage;

(vi) a -R ² -Z ² -R ² - concentration, (vii) a -C (R ⁴⁾ (R ¹³⁾ - [C (= O) -N (R ¹⁰⁾ -C (R ⁵⁾ ( R ¹¹ )] - connection or (viii) -L ⁵ -L ⁵ -L ² - connection,

L ² is -NR ⁵ -C (= Z) -NR ⁵ -, -C (= Z) -NR ⁵ -, -C (= O) -,

-C (= Z) -O-, -NR ⁵ -C (= Z) -, -Z-, -SO ² -, -NR ⁵ -, -SO 2 -NR ⁵ -,

-NR ⁵ -SO ₂ -, -NR ⁵ -C (= O) -O-, -O-C (= O) -, or -O-C (= O) -NR ⁵ linkage,

L ⁵ represents a heteroaryldiyl group,

-NR ⁵ -C (= Z) -NR ⁵ -, -C (= Z) -NR ⁵ -, -C (= Z) -O-, -NR ⁵ -C (= Z) -, -Z-, -S0m-, -NR ⁵ -, -SO 2 NR ⁵ -, -NR ⁵ -SO ₂ -, -NR ⁵ -C (= O) -0-,

-O-C (= O) -, or -O-C (= O) -NR ⁵ - linkage, represents a direct bond, an alkylene group, an alkenylene group or an alkynylene group;

And L ⁵ independently each represent a direct bond or an alkylene group, represents a cycloalkylene or heterocycloalkylene group,

Y ¹ and independently of one another each represent a hydrogen atom, an alkenyl group, an alkyl group, an aryl group, an arylalkyl group, a cycloalkyl group, a heteroaryl group or a heteroarylalkyl group, or -NY ^X Y may form a cyclic amine, and Y ⁵ each independently represents a hydrogen atom, an alkenyl group, an alkyl group, an alkynyl group, an aryl group, a cycloalkenyl group, a cycloalkyl group, a heteroaryl group, a heterocycloalkyl group, or an alkyl group substituted with an alkoxy group, aryl group, cyano group, cycloalkyl group, heteroaryl group , heterocycloalkyl, hydroxy, oxo, -NY ^A Y ^Z , or one or more -CO ₂ R groups

or -C (= O) -NY 2 Y ² , or NY ⁴ Y 2 may form a 5- to 7-membered cyclic amine, which (i) may be optionally substituted with one or more substituents selected from the group consisting of alkoxy, carboxamide, carboxy , hydroxy, oxo (or a five-membered, six-membered, or seven-membered cyclic acetal derivative), R ¹⁰ ;

(ii) may also contain another heteroatom selected from the group consisting of O, S, SO 2, or NY 2; and (iii) may also be fused to other aryl, heteroaryl, heterocycloalkyl or cycloalkyl rings to form a bicyclic or tricyclic ring system,

Y4 represents a hydrogen atom, an alkyl group, an aryl group, an arylalkyl group, a -C (= O) -R ^ ⁴ , -C (= O) -OR ¹⁴ or -SO ₂ R ^{14 group} ,

Z represents an oxygen or sulfur atom, · Z represents a group C (R ²⁾ (R ²⁾ C (= 0) or CH (OH);

Z ² is O, S (O) _n , NR ⁵ , SONR ⁵ , C (= O) NR ⁵ or C (= O);

7? represents a direct bond, C (= O), OC (= O), NR 4 C (= O), or

S0 ₂ ;

m is 1 or 2, n is zero or 1 or 2, and p is zero or 1 to 4,

Y represents a carboxy group (or bioisosteric acid), and the corresponding N-oxides and prodrugs thereof, and pharmaceutically acceptable salts and solvates (such as hydrates) of these compounds and their N-oxides and prodrugs, but excluding compounds where the atom is oxygen, nitrogen or sulfur attached directly to the carbon-carbon multiple bond of an alkenylene, alkynylene or cycloalkenylene moiety.

As used herein, the term compound of the invention and equivalent terms are those of formula (I) as described and defined hereinabove and include prodrugs protected, derivatives of these compounds of formula (I) containing one or more acidic functional groups and / or amino acid side chains, pharmaceutically acceptable salts and solvates, such as hydrates, where possible in the context. Similarly, the term intermediates, whether or not as such protected by the claims, include their salts and solvates where this is possible in the context. For the sake of clarity and clarity, individual cases where indicated in the context are indicated directly in the text, but these are merely illustrative and do not exclude other forms as far as possible in the context.

As used herein, certain terms are used in the description of the present invention, the meaning of which, unless otherwise specifically stated, is as follows.

The term patient refers to both a human individual and other mammals.

By bioisosteric acid (or acidic bioisoster) is meant a group that is chemically and physically similar and exhibits substantially similar biological properties to the carboxy group (Lipinski, Annual Reports in Medicinal Chemistry, 1986, 21, p. 283 Bioisosterism In Drug). Design, Yun, Hwahak Sekye, 1993, 33, pp. 576-579 Application of Bioisosterism To New Drug Design, Zhao, Huaxue Tongbao, -1995, pp. 34-38,

Bioisosteric Replacement And Development Of Lead Compounds In Drug Design, Ab initio Electronic Distributions In Bioisosteres). Examples of suitable acid bioisosteres include: -C (= O) -NHOH-, -C (= O) -CT, OH,

-C (= O) -CH2SH, -C (= O) -NH-CN, sulfo, phosphono, alkylsulfonylcarbamoyl, tetrazolyl, arylsulfonylcarbamoyl, heteroarylsulfonylcarbamoyl,

N-methoxycarbamoyl,

3-hydroxy-3-cyclobutene-1,2-dione group,

3,5-dioxo-1,2,4-oxadiazolidinyl or heterocyclic phenol groups such as

3-hydroxyisoxazolyl and 3-hydroxy-1-methylpyrazolyl.

By acidic functional group is meant a group with acidic hydrogen. Corresponding protected derivatives are derivatives in which the acidic hydrogen atom is replaced by a suitable protecting group. An example of a suitable protecting group is T.W. Greene and P.G.M. Wuts Protective Groups in Organic Chemistry John Wiley and Sons, 1991. As an example

Acidic functional groups include carboxyl (and bioisosteric acid), hydroxy, mercapto, and imidazole. An example of a protected derivative is an ester of a carboxy group (i.e., -CCR ^R ^) _; hydroxy ethers (i.e., -0r14) _? thioethers of mercapto groups (i.e., -SR 4) and N-benzyl derivatives of imidazoles.

The term acyl group refers to the group H-CO- or alkyl-CO-, in which the alkyl group has the same meaning as defined herein.

The term acylamino refers to an acyl-NH- group wherein acyl has the same meaning as defined herein.

A hydrocarbon group containing a carbon-carbon double bond, which group may have a straight or branched chain and contain about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups include groups having from 2 to about 12 carbon atoms in the chain, and more preferably an alkenyl group having from about 2 to about 4 carbon atoms in the chain. Branched throughout is meant that one or more lower alkyl groups, such as methyl, ethyl or propyl, in this case linear alkenyl, are attached to the linear chain. By lower alkenyl is meant a group as defined above containing about 2 carbon atoms to about 4 carbon atoms in the chain, which may be straight or branched. Exemplary alkenyl groups include ethenyl, propenyl, n-bulenyl, and the like. I-Butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl.

By alkenylene is meant an aliphatic divalent radical derived from a straight or branched chain alkenyl group in which the alkenyl group has the same meaning as defined herein. Examples of alkenylene groups include vinylene and propylene.

The term alkoxy refers to an alkyl-O- group in which the alkyl group has the same meaning as defined herein. Examples of alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, and heptoxypropyl.

The term alkoxycarbonyl means an alkyl-O-CO- group in which the alkyl group has the same meaning as previously defined. Examples of alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl.

The term "alkyl", unless otherwise specified, refers to an aliphatic hydrocarbon group which may be straight or branched chain containing from about 1 to about 15 carbon atoms in the chain, optionally substituted with alkoxy or one or more halogen atoms. A particular example of an alkyl group is an alkyl group having from about 1 to about 6 carbon atoms. The term lower alkyl refers to a group or part of a lower alkoxy group; 9 9 9 9 4 4 99 9 9499 494 9 9 9 9 4 9 4 9

449 94 49 4 44 499 lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl, unless otherwise specified, an aliphatic hydrocarbon group which may have a straight or branched chain containing from about 1 to about 4 carbon atoms in the chain. Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, 3-pentyl, heptyl , octyl, nonyl, decyl and dodecyl.

The term alkylene group refers to an aliphatic divalent radical derived from a straight or branched chain alkyl group having 1 to 6 carbon atoms in which the alkyl group has the same meaning as defined herein. Examples of alkylene groups include methylene, ethylene and trimethylene.

The term alkylenedioxy refers to a Ο-alkyl-O- group in which the alkyl group has the same meaning as defined herein. Examples of alkylenedioxy groups are methylenedioxy and ethylenedioxy.

The term alkylsulfinyl means an alkyl-SO- group in which the alkyl group has the same meaning as defined herein. Preferred alkylsulfinyl groups include those in which the alkyl group contains 1 to 4 carbon atoms.

The term alkylsulfonyl group refers to a mini group

9 ·· • · · · 9 9 9 ^: 9 O • 9 ' 9 9 • • • · · · · 9 9 9 9 9 • • · '· • 9 • • 9 9 9 • • 9 9 9 »

alkyl-SO2 'in which the alkyl group has the same meaning as defined herein. Preferred alkylsulfonyl groups include those in which the alkyl group contains 1 to 4 carbon atoms.

The term alkylsulfonylcarbamoyl refers to an alkyl-SO 2 NH-C (= O) - group in which the alkyl group has the same meaning as defined herein. Preferred alkylsulfonyl groups include those in which the alkyl group contains 1 to 4 carbon atoms.

The term alkylthio refers to an alkyl-S- group in which the alkyl group has the same meaning as defined herein. Examples of alkylthio groups include methylthio, ethylthio, isopropylthio and heptylthio.

By alkynyl is meant an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which group may be straight or branched chain and contains about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups include groups having from 2 to about 12 carbon atoms in the chain, and more preferably an alkynyl group having from about 2 to about 4 carbon atoms in the chain. Examples of alkynyl groups include ethynyl, propynyl, n-butynyl, i-butynyl,

3-methylbut-2-ynyl and n-pentinyl.

By alkynylene is meant an aliphatic divalent radical derived from an alkynyl group having 2 to 6 carbon atoms. Examples of alkynylene groups include ethynylene and propynylene.

By amino acid side chain is meant a substituent that is found on the carbon between amino and carboxy groups of α-amino acids. Examples of corresponding protected amino acid side chain derivatives can be found in T. W. Greene and P.G.M. Wuts Protective Groups in Organic Chemistry, John Wiley & Sons, 1991.

The term "aroyl" refers to an aryl-CO- group in which the aryl group has the same meaning as previously defined. Examples of aroyl groups include benzoyl and 1-naphthoyl and 2-naphthoyl.

is meant a group as defined by the term aroylamino group aroyl-NH-, wherein aroyl has the same definition as defined herein.

The term aryl as a separate group or as part of a group means:

(i) an optionally substituted monocyclic or multicyclic aromatic carbocyclic moiety containing from about 6 to about 14 carbon atoms, such as a phenyl group or a naphthyl group, or (ii) an optionally substituted partially saturated multicyclic aromatic carbocyclic moiety in which they are aryl and the cycloalkyl or cycloalkenyl moiety together condensed to form a cyclic structure such as a tetrahydronaphthyl ring, an indenyl ring or an indanyl ring. Aryl groups may be substituted with one or more aryl group substituents, which may be the same or different, among which substituents

9 9 · · ·

Aryl groups include, for example, acyl, acylamino, alkoxy, alkoxycarbonyl, alkylenedioxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxy, arylalkyloxy, arylalkyloxy, arylalkyloxy arylsulfinyl, arylsulfonyl, arylthio, carboxy, cyano, halogen, heteroaroyl, heteroaryl, heteroarylalkyloxy, heteroaroylamino, heteroaryloxy, hydroxy, nitro, trifluoromethyl, YY Y-, Y-, Y-, Y-, Y-, Y ^ SC ^ -, Y-Y-alkylene-Z ⁴ - (in which the alkylene moiety contains 2 to 6 carbon atoms, and Z ⁴ is O, NR ⁵ or S (0) _n) alkyl-C (= O) -Y-N-N, alkylSO ₂ -Y ¹ N-or alkyl optionally substituted with aryl u, heteroaryl, hydroxy or YY N-.

The term "arylalkenyl" refers to an aryl-alkenyl group in which the aryl and alkenyl groups have the same meaning as defined herein. Preferred arylalkenyl groups contain a lower alkenyl moiety. Examples of arylalkenyl groups include styryl and phenylallyl.

The term "arylalkyl" refers to an aryl-alkyl group in which the aryl and alkyl groups have the same meaning as defined herein. Preferred arylalkyl groups contain an alkyl moiety having 1 to 4 carbon atoms. Examples of arylalkyl groups include benzyl, 2-phenethyl, and 9,999,999. And a naphthalenemethyl group.

The term arylalkyloxy refers to an arylalkyl-O group in which the arylalkyl groups have the same meaning as defined herein. Examples of such arylalkyloxy groups include benzyloxy and 1-naphthalenmethoxy or 2-naphthalenmethoxy.

The term arylalkyloxycarbonyl means an arylalkyl-O-CO- group in which the arylalkyl groups have the same meaning as defined herein. An example of an arylalkyloxycarbonyl group is benzyloxycarbonyl.

The term "arylalkylthio" refers to an arylalkyl-S group in which the arylalkyl group has the same meaning as defined herein. An example of an arylalkylthio group is benzylthio.

The term arylalkynyl refers to an aryl-alkynyl group in which the aryl and alkynyl groups have the same meaning as defined herein. Examples of such arylalkynyl are phenylethynyl and 3-phenylbut-2-ynyl.

By arylene group is meant an optionally substituted divalent radical derived from an aryl group. Examples of arylene groups include an optionally substituted phenylene group, a naphthylene group, and an indanylene group. When Ar 1 is an arylene group, this group may specifically represent an optionally substituted phenylene group. Suitable substituents include one or more aryl group substituents as defined above, in particular halogens, methyl or methoxy.

The term "aryloxy" refers to an aryl-O- group in which the aryl moiety has the same meaning as defined herein. Examples of aryloxy are optionally substituted phenoxy and naphthoxy.

The term aryloxycarbonyl refers to an aryl-O-C (= O) - group in which the aryl moiety has the same meaning as defined herein. Examples of aryloxycarbonyl include phenoxycarbonyl and naphthoxycarbonyl.

The term arylsulfinyl group refers to the aryl-SO- group in which it has. an aryl moiety having the same meaning as defined herein.

The term "arylsulfonyl" refers to an aryl-SO 2 - group in which the aryl moiety has the same meaning as defined herein.

The term arylsulfonylcarbamoyl group refers to an aryl-SO2-NH-C (= O) - group in which the aryl moiety has the same meaning as defined herein.

The term arylthio refers to an aryl-S- group in which the aryl moiety has the same meaning as defined herein. Examples of arylthio are phenylthio and naphthylthio.

The term azaheteroaryl group means aromatic

a carbocyclic moiety containing about 5 to about 10 ring members, one of which ring members is nitrogen and the other ring members are selected from the group consisting of carbon, oxygen, sulfur and nitrogen. Examples of such azaheteroaryl groups include pyridyl, pyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl, imidazolyl and benzimidazolyl.

The term azaheteroaryldiyl group refers to an optionally substituted divalent group derived from a heteroaryl group.

By cyclic amine is meant a 3- to 8-membered monocyclic cycloalkyl ring system in which one of the carbon atoms in the ring is replaced by nitrogen, w-w.-J (i) may optionally contain another heteroatom selected and i.

from the group consisting of O, S or NY (wherein Y ^J represents a hydrogen atom, an alkyl group, an arylalkyl group and an aryl group); and (ii) may be fused to another aryl or heteroaryl ring to form a bicyclic ring system. Examples of such cyclic amines are pyrrolidine, piperidine, morpholinyl, piperazine, indoline and pyrindoline.

By cycloalkenyl is meant a non-aromatic monocyclic or multi-cyclic ring system containing at least one carbon-carbon double bond containing about 3 to about 10 carbon atoms. Examples of such monocyclic cycloalkenyl rings are cyclopentenyl, cyclohexenyl or cycloheptenyl.

The term cycloalkenylalkyl means a cycloalkenyl-alkyl group in which the cycloalkenyl and alkyl moieties have the same meaning as defined herein. Examples of cycloalkenylalkyl groups are cyclopentenylmethyl, cyclohexenylmethyl or cycloheptenylmethyl.

The term cycloalkenylene refers to a divalent radical derived from an unsaturated monocyclic hydrocarbon containing from about 3 to about 10 carbon atoms by removing the hydrogen atom from each of the two different ring carbon atoms. Examples of cycloalkenylene groups are cyclopentenylene and cyclohexenylene.

The term cycloalkyl refers to a saturated monocyclic or bicyclic ring system containing from about 3 to about 10 carbon atoms, optionally substituted with an oxo group. Exemplary monocyclic cycloalkyl rings include C 3 -C 8 cycloalkyl rings such as cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term cycloalkylalkenyl refers to a cycloalkyl-alkenyl group in which the cycloalkyl moiety and the alkenyl moiety have the same meaning as defined herein. Examples of monocyclic cycloalkylalkenyl groups include cyclopentylvinylene and cyclohexylvinylene.

0 0 0 ·· • 0 * 0 00 0 0 • 0 0 0. »· 0 0 0 0 0 0 0 0 • 0 0 0 0 • 0 0 · 0 · 0 0 0 0 0

The term cycloalkylalkyl refers to a cycloalkyl-alkyl group in which the cycloalkyl moiety and the alkyl moiety have the same meaning as defined herein. Exemplary monocyclic cycloalkylalkyl groups include cyclopentylmethyl, cyclopropylmethyl, cyclohexylmethyl and cycloheptylmethyl.

The term cycloalkylalkynyl is a mini cycloalkyl-alkynyl group in which the cycloalkyl moiety and the alkynyl moiety have the same meaning as defined herein. Examples of monocyclic cycloalkylalkynyl groups include cyclopropylethynyl, cyclopentylethynyl and cyclohexylethynyl.

By cycloalkylene is meant a divalent radical derived from a saturated monocyclic hydrocarbon containing from about 3 to about 10 carbon atoms, which is obtained by removing a hydrogen atom from each of the two different ring carbon atoms. Examples of such cycloalkylene groups include cyclopentylene and cyclohexylene.

The term halo or halogen means a fluorine, chlorine, bromine or iodine atom. It is preferably fluorine or chlorine.

The term heteroaroyl refers to a heteroaryl-C (= O) - group in which the heteroaryl group has the same meaning as defined herein. As an example of this

heteroaroyl groups include pyridylcarbonyl.

The term heteroaroylamino is a heteroaroyl-NH- group in which the heteroaryl moiety has the same meaning as defined herein.

The term heteroaryl group refers to both a group and a portion of a group which means:

(i) an optionally substituted aromatic monocyclic or multicyclic organic moiety containing about 5 to about 10 ring members wherein one or more of the ring members is (or is) a member (s) other than a carbon atom, such as a nitrogen atom, oxygen or sulfur (for example, benzimidazolyl, benzthiazolyl, furyl, imidazolyl, indolyl, indalizinyl lineam isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl, which may optionally be substituted by one or more aryl group substituents as defined above e, (ii) an optionally substituted partially saturated multicyclic heterocarbocyclic moiety wherein the heteroaryl and cycloalkyl or cycloalkenyl groups are fused together to form a cyclic structure (an example of which is pyrindanyl). Optional substituents are one or more

aryl group substituents as defined above. When or ΐΛ contains an optionally substituted heteroaryl group, this moiety may in particular represent an optionally substituted azaheteroaryl group.

The term heteroarylalkenyl means a mini heteroaryl-alkenyl group in which the heteroaryl and alkenyl moieties have the same meaning as previously defined. Preferred heteroarylalkenyl groups contain a lower alkenyl group. Examples of heteroarylalkenyl groups include pyridylethenyl and pyridylallyl.

The term heteroarylalkyl refers to a heteroaryl-alkyl group in which the heteroaryl moiety and the alkyl moiety have the same meanings as defined above. Preferred heteroarylalkyl groups contain an alkyl group having 1 to 4 carbon atoms. Exemplary heteroarylalkyl groups include pyridylmethyl.

The term heteroarylalkoxy refers to a heteroarylalkyl-O- group in which the heteroarylalkyl group has the same meaning as defined herein. An example of a heteroaryloxy group is an optionally substituted pyridylmethoxy group.

The term heteroarylalkinyl means a mini heteroaryl-alkynyl group in which the heteroaryl and alkynyl groups have the same meaning as defined herein. Examples of heteroarylalkenyl groups include pyridylethynyl and α aidyφφφφφ]]]]]] ]idyidyidyidyidyidyidyidyidyidyidyidyidyidyidy idyidyidyidyidyidyidyidyidyidyidyidyidyidyidyidyidyidyidyidyidyidyidyidyidyidyidyidyidyidyidyidyidyidyidyidyidyidyidyidyidyidyidyidyidyidyidyidyidy

3-pyridylbut-2-ynyl.

By a heteroaryldiyl group is meant a divalent radical derived from an aromatic monocyclic or multicyclic organic moiety containing about 5 to about 10 ring members in which one or more of the ring members are (or is) elements (or an element) other than a carbon atom, for example, nitrogen, oxygen or sulfur, and optionally is substituted with one or more aryl group substituents as defined herein. When Ar 1 is an optionally substituted heteroaryldiyl group, the group may be an optionally substituted azaheteroaryldiyl group.

The term heteroaryloxy refers to a heteroaryl group in which the heteroaryl group has the same meaning as previously defined. An example of a heteroaryloxy group is an optionally substituted pyridyloxy group.

The term heteroarylsulfonylcarbamoyl refers to a heteroaryl-SO2-NH-C (= O) - group in which the heteroaryl group has the same meaning as previously defined.

The term heterocycloalkyl means:

(i) a cycloalkyl group having about 3 to about 7 ring members which contains one or more heteroatoms selected from oxygen, sulfur or NY and which may be optionally substituted by an oxo group, (ii) an optionally substituted partially saturated multicyclic heterocarbocyclic moiety wherein the aryl ring (or heteroaryl ring) and the heterocycloalkyl group are together fused to form a cyclic structure

W ~; · 99

9 '· 9 · • ··

(Examples of such groups include chromanyl, dihydrobenzofuranyl, indolinyl, and pyrindolinyl).

The term heterocycloalkylalkyl means a heterocycloalkyl-alkyl group in which the heterocycloalkyl moiety and the alkyl moiety have the same meaning as previously defined.

The term "heterocycloalkylene" refers to a divalent radical derived from a saturated monocyclic hydrocarbon containing from about 5 to about 7 carbon atoms and containing one or more heteroatoms selected from the group consisting of oxygen, sulfur and NY and optionally substituted by an oxo group; by removing the hydrogen atom from each of the two different atomic atoms in the ring, or when NY * 'is NH by removing the hydrogen atom from one ring carbon atom and the hydrogen atom from that NH group, or if α the ring contains two NY ^J heteroatoms and NY ^- 'NH means removal of the hydrogen atom from both nitrogen atoms.

When ϊΛ is a heterocycloalkylene group, this group may in particular represent a bivalent radical derived from pyrrolidine, in particular 3,4-pyrrolidinediyl.

By prodrug is meant a compound that is convertible in vivo by metabolic means (such as hydrolysis) to a compound of formula I, including N-oxides thereof. For example, an ester of a compound of formula I containing a hydroxy group can be converted by hydrolysis in vivo to the parent molecule. Alternatively, the ester of a compound of Formula I containing a carboxy group may be convertible by in vivo hydrolysis

to the base molecule.

Suitable hydroxyl-containing esters of the compounds of formula (I) include, for example, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-p-hydroxynaphthoates, gentisate, isothionates, di-p-toluoyltartrate , methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and quinates.

Suitable carboxy-containing esters of the compound of formula (I) include, for example, those described in F.J. Leinweber, DrugMetab. Res., 1987, 18, 379.

Suitable esters of the compounds of formula I containing both a carboxy group and a hydroxy group in the-části-Υ- moiety include lactones formed by the loss of water between said carboxy group and the hydroxy group. Examples of lactones include caprolactones and butyrolactones.

A particularly suitable group of hydroxyl-containing esters of the compounds of formula (I) may be obtained from acid moieties selected from Bundgaard et al., J. Med. Chem., 1989, 32, 2503-2507, which may include substituted (aminomethyl) benzoates, for example dialkylaminomethylbenzoates, in which two alkyl groups may be joined together and / or interrupted by an oxygen atom or optionally substituted a nitrogen atom, for example an alkylated nitrogen atom, in particular (morpholino-methyl) benzoates, such as e.g.

9 1 9 »· 9,999

9 9 9 «9 9

999 99 9

9 9 9 9 9

999 98 99 «99 9

3- (morpholinomethyl) benzoates or

4- (morpholinomethyl) benzoates a

4- (alkylpiperazin-1-yl) benzoates, such as, for example

3- (4-alkylpiperazin-1-yl) benzoates;

4- (4-alkylpiperazin-1-yl) benzoates.

In cases where the compounds of the present invention contain a carboxy group or a sufficiently acidic bioisoster, base addition salts can be readily obtained, which base addition salts are convenient for use and, in practical use, the salt form itself the same use as the free acid forms. Bases which may be used to prepare these base addition salts include those which, when combined with the free acid, provide pharmaceutically acceptable salts, i.e., salts whose cations are non-toxic to the patient in a pharmaceutically applied form. doses of these salts, so that the beneficial inhibitory effect inherent in the free base is not diminished by the side effects that occur due to the presence of cations. Pharmaceutically acceptable salts, including those derived from the alkali or alkaline earth metals within the scope of the present invention, include those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, hydroxide aluminum, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine,

N-methylglucamine, lysine, arginine, ornithine, choline,

Ν, N--dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris (hydroxymethyl) aminomethane, tetramethylammonium hydroxide and the like.

4 »4 4 ·· ··· 444444 • 44 ·

4 »·

Some of the compounds of the present invention are basic and are useful in the form of the free bases or in the form of pharmaceutically acceptable acid addition salts thereof.

Acid addition salts are a more convenient form for use, and in practice the use of these salts is the same as the use of the free base form. Acids which can be used to prepare these acid addition salts preferably include those which, when combined with the free bases, provide pharmaceutically acceptable salts, i.e. salts whose cations are nontoxic to the patient at pharmaceutically administered doses of these salts, thus, the beneficial inhibitory effect inherent in the free base is not diminished by the side effects that occur due to the presence of cations. While pharmaceutically acceptable salts of said basic compounds are preferred, all acid addition salts are used as sources of the free base forms, unless the specific salt per se is not only required as an intermediate, such as when the salt is obtained only for purification and identification, or when used as an intermediate in the preparation of a pharmaceutically acceptable salt by ion exchange procedures. Pharmaceutically acceptable salts, including those derived from mineral acids and organic acids within the scope of the present invention, include hydrohalides such as hydrochlorides and hydrobromides, sulfates, phosphates, nitrates, sulfamates, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-β-hydroxynaphthoates, gentisates, • *

0 0 0 0 0 0000 isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and quinates.

Salts of the compounds of the present invention are both suitable as such as active compounds and are useful for purification purposes, for example, to extend the solubility range between the salt and the parent compound, by-products and / or starting materials using methods commonly known in the art. prior art.

With respect to the compounds of formula (I) above, the following groups of compounds are particularly preferred:

i 3 3> 3

In particular, R ¹ may be an R -Z - group in which Z has the same meaning as defined above, in particular and has the same meaning as defined above, in particular (i) an optionally substituted aryl group such as an optionally substituted phenyl group optional substituents are aryloxy, cyano, halogen (such as chlorine or fluorine), lower alkoxy (such as methoxy), lower alkyl (such as methyl), nitro and perfluoro-lower-alkyl (such as trifluoromethyl) (ii) optionally substituted heteroaryl, such as isoquinolinyl, isoxazolyl, pyrazolopyrimidinyl, pyridyl, pyrimidinyl, quinolinyl, thiazolyl, and triazolyl, each of which may be optionally substituted with one or and more aryl substituents as defined above

* e · • • e

[preferred optional substituents include alkyl-C (= O) -, aryl, cyano, halogens (such as chlorine or fluorine), lower alkoxy (such as methoxy), lower alkyl (such as methyl) a lower alkylsulfonyl group, a lower alkylthio group, a nitro group and a perfluoro-lower-alkyl group (such as a trifluoromethyl group) or (iii) an optionally substituted arylalkyl group in which the aryl group is optionally substituted with one or preferably two aryl group substituents (between preferred optional substituents include halogens, hydroxy and methoxy).

In particular, R ^x may be an R -C (= O) - group in which R 6 represents a substituted aryl group selected from the group consisting of 2-chlorophenyl,

5-chloro-2-cyanophenyl, 2-chloro-6-methylphenyl, 2,6-dichlorophenyl, 2,6-difluorophenyl, 4-fluoro-2-trifluoromethyl,

2-methyl-4-nitrophenyl, 2-methyl-5-nitrophenyl, 2-nitrophenyl, 3-nitrophenyl,

A 2-phenoxyphenyl group or an optionally substituted heteroaryl group selected from quinolin-4-yl, isoquinolin-2-yl,

2,4-pyridin-3-yl,

2,6-dimethyl-4-trifluoromethylpyridin-3-yl;

A 4-trifluoromethylpyridin-3-yl group,

A 2-phenyl-4-methyl-1,2,3-triazol-5-yl group,

3,5-dimethylisoxazol-4-yl;

A 2,7-dimethylpyrazolo [1,5-a] pyrimidin-6-yl group,

2-isopropyl-4-methylthiazol-5-yl,

A 4-trifluoromethylpyrimidin-5-yl group, a 4-hydroxybenzyl group, a 3-chloro-4-hydroxybenzyl group, and a pharmaceutically acceptable salt thereof;

3-fluoro-4-hydroxybenzyl and 4-hydroxy-3-methoxybenzyl.

r! it may also in particular be a group R 1 -L 1 -Ar 1 -L ⁴ -Z 1 - in which

7? has the same meaning as described above, in particular

C (= 0)

L ⁴ represents a straight or branched chain alkylene group having 1 to 6 carbon atoms, preferably a straight chain alkylene group having 1 to 4 carbon atoms, such as a methylene group or an ethylene group, preferably a methylene group,

Ar 6 represents an optionally substituted phenylene group such as an optionally substituted m-phenylene group or a p-phenylene group, preferably an optionally substituted p-phenylene group, more preferably a 3-substituted p-phenylene group in which the substituent is in the ortho position to place the R 1 -L 1 - group, (preferred optional substituents include halogens, C 1 -C 4 alkyl groups, C 1 -C 4 alkoxy groups, C 1 -C 4 alkylthio groups, C 1 -C 4 alkylsulfinyl groups C 1 -C 4 alkyl and C 1 -C 4 alkylsulfonyl, especially suitable substituents are chlorine, methyl, methoxy, methylthio, methylsulfinyl and methylsulfonyl), or Ar 1 represents an optionally substituted heteroaryldiyl group, such as optionally subst an ituated azaheteroaryldiyl group (such as an optionally substituted pyridinediyl group, preferably a p-pyridinediyl group), wherein, if desired, an o-o-;

The substituents include, for example, an alkyl group having 1 to 4 carbon atoms and an alkoxy group having 1 to 4 carbon atoms. particularly preferred is methyl and methoxy, particularly preferred is pyridine-2,5-diyl in which the R-L-group is adjacent to the pyridyl nitrogen atom, which group is substituted in the

4-position or 6-position by methyl or methoxy means -NH-C (= O) -NH-, and has the same meaning as given above, especially an optionally substituted aryl group (such as an optionally substituted phenyl group) or an optionally substituted heteroaryl group (such as an optionally substituted pyridyl group, preferably 2-methyl (or methoxy) phenyl or 3-methyl (or methoxy) phenyl, more preferably 2-methylphenyl or

3-methyl-2-pyridyl.

In particular, R ^ may also be R ^ -L ^ -Ar--L ^ -Z - - in which:

has the same meaning as previously defined, in particular C (= O), represents a straight or branched chain alkylene group having 1 to 6 carbon atoms, in particular a straight chain alkylene group having 1 to 4 carbon atoms such as methylene, for example a group or ethylene group, preferably a methylene group,

Ar ^ · means an eight- to ten-membered bicyclic system ----->. In which:

(i) the ring is a 5- or 6-membered optionally substituted heterocycle, preferably a 5-membered heteroaryl ring, (ii) a ring

means a five or six membered optionally substituted heterocycle or an optionally substituted benzene ring, preferably a benzene ring, (iii) each ring is optionally substituted with one or more aryl group substituents as defined above, (iv) the two rings are joined together by a carbon- carbon or carbon-nitrogen, the system

is preferably optionally substituted by a benzoxazolyl group or optionally substituted

benzimidazolyl, each [in particular the ring is optionally substituted with one or more aryl substituents as defined above [as examples of particular aryl substituents include lower alkyl (such as methyl), lower alkoxy (such as methoxy) , amino, halogens, hydroxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, nitro or trifluoromethyl];

L is NR, especially NH, and

R 6 has the same meaning as defined above, in particular an optionally substituted aryl group such as a 2-substituted phenyl group [examples of particular aryl substituents include a lower alkyl group (such as a methyl group), a lower alkoxy group (such as such as methoxy), halogens (such as fluorine or chlorine) and YY N- (such as dimethylamino)], and is preferably 2-methylphenyl.

Substituent r! it may also in particular be a group R 1 -L 2 -Ar 2 -L 2 -Z 2 - in which:

it has the same meaning as previously defined, in particular it represents a group C (= O), ΐΛ represents an alkylene group containing 1 to 6 atoms

a straight or branched-chain carbon, in particular a C1-C4 alkylene group, such as a methylene group or an ethylene group, preferably a methylene group,

Ar ³ · represents an optionally substituted phenylene, such as optionally substituted m-phenylene or p-phenylene, preferably optionally substituted p-phenylene, more preferably a 3-substituted p-phenylene, in which the substituent ortho to R-L - (preferred optional substituents include chlorine, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl C 1 -C 4 alkyl and C 1 -C 4 alkylsulfonyl, especially chloro, methyl, methoxy.

or Ar ⁴ represents an optionally substituted heteroaryldiyl group, such as an optionally substituted azaheteroaryldiyl group (e.g., an optionally substituted pyridindiyl group, preferably a p-pyridindiyl group), in which the optional substituents include an alkyl group containing up to 4 carbon atoms and an alkoxy group having 1 to 4 carbon atoms, in particular a methyl group and a methoxy group, and more preferably a pyridine-2,5-diyl group, and wherein R-L- is adjacent to the nitrogen atoms of the pyridyl moiety wherein it is substituted at the 4-position or the 6-position by a methyl or methoxy group,

Lv is -C (= O) -NH-, a

R is a heterocycloalkyl group, in particular a bicyclic amino group containing from 9 to 10 atoms,

- t · *:

Preferably an indolinyl group.

In particular, R can be hydrogen.

In particular, R may also represent a lower alkyl group (such as a methyl group).

O

In particular, the substituent R may also be a lower alkoxy group (such as a methoxy group).

In particular, the substituent may be an unsubstituted C 1 -C 3 alkylene chain such as methylene, ethylene and trimethylene, especially methylene or ethylene.

The substituent may particularly represent a group C (R ⁷⁾ (R ^7a), especially such groups in which R ⁷ and R ⁷ represent both hydrogen i.

The substituent 1A may in particular be an optionally substituted alkylene group, in particular an optionally substituted ethylene group or a propylene group, preferably an optionally substituted ethylene group. Preferred substituents include lower alkyl, aryl, heteroaryl, -N (R ⁸ ) -C (= O) -R ⁹ , -N (R ⁸ ) -C (= O) - OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ , -ny ⁴ y ⁵ a - [C (= O) -NR ¹ R) -C (r ⁵ ) (R ¹¹ )] p C (= O) - NY ⁴ Y ⁵ or an alkyl group substituted with a carboxy group (or an acidic bioisoster), -ZH, -ZR ³ , -C (= O) -NY ⁴ Y ⁵ or -NY ⁴ Y ⁵ . In one preferred embodiment, L ¹ is a group

-C-CH ₉ I

R ¹⁵ [in which:

a hydrogen atom or a lower alkyl group (such as a methyl group); and

· R * represents a hydrogen atom or a lower alkyl group, or R5 represents hydrogen and R @ ¹ represents aryl, heteroaryl, -N (R c) -C (= 0) -R, -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO 2 -R ⁹ , -NY ⁴ Y ⁵ or - [C (= O) -N (R ¹¹ ) -C (R ⁵ ) ( R ¹¹ )] p C (= O) -NY ⁴ Y ⁵ or is an alkyl group substituted with carboxy (or an acidic bioisoster), -ZH, -ZR ⁸ , -C (= O) -NY ⁴ Y ⁸ or -NY ⁴ Y ⁴ ], and is preferably a group

in particular CH-CK ₂ (15 [in which R ¹⁸ is hydrogen, lower alkyl, aryl, heteroaryl, -N (R ⁸ ) -C (= O) -R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ or -ΝΥ ⁴ γ ⁵ or an alkyl group substituted with a carboxy group, -OH, -OR ⁸ or -C = O) -NY ⁴ Y ^4; ].

In another preferred embodiment, ΐΛ is -CH-, -C-

15a [in which:

R ⁸ represents a hydrogen atom or a lower alkyl group (such as a methyl group), and

4 * 4 · • · * i, · · · · · * • · ft · 4 9 rI ^ ³ · is lower alkyl, or R ³ is hydrogen and R ^3a is aryl, heteroaryl, - N (R 0) -C (= O) -R, -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ , -NY ⁴ Y ⁵ or - [C (= O) -N (R ¹⁹ ) -C (R ³ ) (R ¹¹ )] p C (= O) -NY ⁴ Y ³ or is an alkyl group substituted with a carboxy group (or an acidic bioisoster), -ZH, -ZR ³ , -C (= O) -NY ⁴ Y ⁵ or -NY ⁴ Y ⁵ ], and preferably is: h.

H-15a in particular a group

-CH.

-CH15a [wherein R ³³ · represents -N (R ⁸⁾ -C (= 0) -R ⁹ or -N (R ⁸⁾ -SO ₂ -R ^9].

In particular, the substituent L ¹ may also represent an unsubstituted alkenylene group, in particular a vinyl group.

In particular, the substituent ΐΛ may also be -Z ² -R ¹² -, such as -O-CH ₂ -, -S (O) _n -CH ₂ -,

-S (O) _n -CH ₂ -CH ₂ -, or especially -NH-CH ₂ -.

In particular, the substituent ΐΛ may also represent a group

-L ³ -L ^ -L ² , in which:

S 7 (i) L ^J and L both represent a direct bond and L g represents an optionally substituted heterocycloalkylene group, such as a pyrrolidinediyl group, in particular

3,4-pyrrolidinediyl, or cycloalkylene, such as cyclopentyl, (ii) L ³ is alkylene, such as methylene, is cycloalkylene, such as cyclopentyl, and L is a direct bond, or ( iii) L ³ is a direct bond, is a cycloalkylene group, such as a cyclopentyl group, and L ² is an alkylene group, such as a methylene group.

In particular, the substituent Y may be a carboxy group.

It is to be understood that all suitable combinations of the individual and preferred groups mentioned above are within the scope of the present invention.

A particularly preferred group of compounds of the present invention are compounds of formula (Ix):

in which:

r! represents a group selected from the group consisting of: (i) R ³ (II) R ³ -L ² -R ⁴ (III) R ² -L ³ -L ⁴ -Arl - and (iv) R ³ -L ³ -Ar ¹ - L ² -R ⁴ -, [in which:

R ³ represents alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkinyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkinyl, cycloalkenyl, heteroalalkenylalkyl, heteroloalkenylalkyl, heteroloalkenylalkyl, heteroloalkenylalkyl, , heteroarylalkynyl heterocycloalkyl or heterocycloalkylalkyl;

L ² is -NR ⁵ -C (= Z) -NR ⁵ -, -C (= Z) -NR ⁵ -, -C (= O) -, -C (= Z) -O-, -NR ⁵ - C (= Z) -, -Z-, -S0-, - S02-, -NR ⁵ -, -SO 2 NR ⁵ -, -NR ⁵ -SO ₂ -, -NR ⁵ -C (= O) -O -, -O-C (= O) -, or -O-C (= O) -NR ⁵ connection,

L ³ represents a heteroaryldiyl group, a heterocycloalkylene group, -NR ⁵ -C (= Z) -NR ⁵ -,

-C (= Z) -NR ⁵ -, -C (= Z) -O-, -NR ⁵ -C (= Z) -, -Z-, -SO-,

-S0 ₂ -, -NR ⁵ -, -SO 2 NR ⁵ -, -NR ⁵ -SO 2, -NR ⁵ -C (= O) -0-,

-O-C (= O) -, or -O-C (= O) -NR ⁵ - join,

L ⁴ represents a direct bond, an alkylene group, an alkenylene group or an alkynylene group or a L ⁵ -NR ⁵ - linkage;

L ⁵ represents a direct bond or an alkylene group,

R ⁴ represents an alkylene group, an alkenylene group or an alkynylene group;

R ⁵ represents a hydrogen atom or a lower alkyl group;

Ar ⁴ represents a phenylene group or a heteroaryldiyl group; and

^f 4

Z represents an oxygen or sulfur atom, but excluding compounds in which an oxygen, nitrogen or sulfur atom is attached directly to a carbon-carbon multiple bond of an alkenylene or alkynylene residue];

represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group;

means a straight chain alkylene group having 1 to 3 carbon atoms optionally substituted by one or more groups selected from the group consisting of alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, amino, oxo, thioxo, or alkyl substituted with -ZR 1, -NY 2 Y ² , -CO ₂ r 6 or -C (= O) -NY 2 Y ² [in which R 1 represents a hydrogen atom, an alkyl group, an alkenyl group, an aryl group, an arylalkyl group, a cycloalkyl group a cycloalkylalkyl group, a heteroaryl group or a heteroarylalkyl group; and Y and Y are each independently hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl, or -NY Y may form heterocycloalkyl], means C (R ²⁾ (R ²⁾ or C (= 0), in which R ² and R ^2a independently each represent hydrogen or lower alkyl},

- 43 ΐΛ denotes (i) a direct bond, (ii) an alkenylene group, alkylene group, alkynylene group, cycloalkenylene group, cycloalkylene group, heteroaryldiyl group, heterocycloalkylene group or arylene group, each of which is optionally substituted with (a) an acidic functional group (or the corresponding protected derivative), R, -C (= O) -R 9, -N (R ⁸ ) -C (= O) -R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸⁾ -SO ₂ -R ^9,

- [C (= O) -N (R ¹⁰ ) -C (R ⁵ ) (R ¹¹ )] _p -C (= O) -NY ⁴ Y ⁵ , or -NY ⁴ Y ⁵ , (b) alkyl substituted an acidic functional group (or the corresponding protected derivative) or -C (= O) -NY ⁴ Y ⁵ or -NY ⁴ Y ⁵ ;

(iii) - [C (= O) -N (R ¹⁰ ) -C (R ⁵ ) (R ¹¹ )] _p - linkage, (iv) -Z ² -R ⁴ - ² - linkage;

(v) -C (= O) -CH 2 C (= O) - linkage;

(vi) -R ¹² -Z ² -R ¹² - linkage, or (vii) -C (R ⁴ ) (R ¹³ ) - [C (= O) -N (R ¹⁰ ) -C (R ⁵ ) (R ¹³ ) ¹¹ )] _p - connections {in which:

R ⁸ is hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;

R ⁹ represents an alkyl group, an aryl group, a cycloalkyl group, a heteroaryl group or a heterocycloalkyl group or an alkyl group substituted with an aryl group, an acidic functional group (or a corresponding protected derivative), a cycloalkyl group, a heteroaryl group, a heterocycloalkyl group

-O ⁴ ,-,-, -ZR ³ -, -C (= O) -NY ⁴ Y ⁵ or -NY ⁴ Y ⁵ ;

R ^ · ® represents a hydrogen atom, R ³ or an alkyl group substituted with an alkoxy group, a cycloalkyl group, a hydroxy group, a mercapto group, an alkylthio group or -NY ⁴ Y ³ ;

r H and R ³ independently of each other are selected from the group consisting of hydrogen and amino acid side chain groups and the corresponding protected derivatives, acidic functional groups (or corresponding protected derivatives), R ³ , -C (= O) -R ³ or

-C (= O) -NY ⁴ Y ³ , or an alkyl group substituted with an acidic functional group (or the corresponding protected derivative), R ³ , -NY ⁴ Y ⁵ , -NH-C (= O) -R ³ , -C (= O) -R ⁴ -NH ₂ ,

-C (= O) -Ar ¹ -NH 2, -C (= O) -R ⁴ -CO ² H or -C (= O) -NY ⁴ Y ⁵ ;

or R ¹ ® and R ¹ * or R ¹ ® and R ¹² together with the atoms to which they are attached form a three to six membered heterocycloalkyl ring,

R ¹² represents an alkylene group having 1 to 6 carbon atoms, optionally substituted with R 12,

Y ⁴ and Y ³ independently each represent hydrogen, alkenyl, alkyl, alkynyl, aryl, cycloalkenyl, cycloalkyl, heteroaryl, heterocycloalkyl, or alkyl substituted by alkoxy, aryl, cyano, cycloalkyl, heteroaryl, heterocycloalkyl,

-hydroxy, oxo, -NY Y, or one or more 9

-9 9.

-CO ₂ R ⁸ or -C (= O) -NY ² , or NY ⁴ Y ⁴ may form a 5- to 7-membered cyclic amine, which (i) may be optionally substituted with one or more substituents selected from the group consisting of alkoxy, carboxamide a group, carboxy, hydroxy, oxo (or a five, six or seven membered cyclic acetal derivative thereof), R ¹⁰ ;

(ii) may also contain another heteroatom selected from

A phy groups comprising O, S, SO ₂ , or NY [wherein Y 0 is hydrogen, alkyl, aryl, aryl, -C (= O) -R ⁴ · ⁴ · ⁴ ,

-C (= 0) -0R ¹⁴ or -S0 ₂ R 1 ⁴ (wherein R ⁴ is alkyl, aryl, aryiaikylovou, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylaikylovou, heterocycloalkyl or heterocycloalkylalkyl group]; and (iii) may also be fused to other aryl, heteroaryl, heterocycloalkyl or cycloalkyl rings to form a bicyclic or tricyclic ring system,

Z ² is O, S (O) _n , NR 4, SONR 4, C (= O) NR ³ or

C (= O);

and p is zero or an integer from 1 to 4}, and

Y is carboxy (or acid bioisostere) or -C (= 0) -NY ⁴ Y ^], and the corresponding N-oxides and their prodrugs, and pharmaceutically acceptable salts and solvates (e.g.

hydrates) of these compounds and their N-oxides and prodrugs.

Another particular group of compounds of the present invention are compounds of formula (Ia):

(wherein R ² , R ³ , A ¹ , Ar ¹ , L ¹ , L ⁴ , Y and Z ^{1 have the} same meaning as previously defined, and the corresponding N-oxides and prodrugs thereof, and pharmaceutically acceptable salts and solvates (such as hydrates) of these and their N-oxides and prodrugs.

According to the invention preferred compounds of formula (Ia) in which R ³ represents optionally substituted aryl, especially optionally substituted phenyl, such as 2-substituted phenyl, especially

2-methylphenyl.

Also preferred according to the invention are the compounds of formula (Ia) in which R represents an optionally substituted heteroaryl group, in particular an optionally substituted pyridyl group, such as an optionally substituted 2-pyridyl group, in particular

2-methyl-2-pyridyl.

Also preferred are compounds of formula (Ia),

»·» ·.

··· ί · · · · · ·

wherein Ar 1 is an optionally substituted phenylene group, especially an optionally substituted m- or p-phenylene group, especially an optionally substituted p-phenylene group. Particularly preferred are compounds of the above formula (Ia) in which Ar 1 is

A 3-substituted p-phenylene group in which said substituent is located ortho to position the group. ? -NH-C (= O) -NH-. Preferred optional substituents include halogens, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, and C 1 -C 4 alkylsulfonyl. carbon atoms, especially chloro, methyl, methoxy, methylthio, methylsulfinyl and methylsulfonyl.

Also preferred are compounds of the above formula (Ia) in which Ar 1 is an optionally substituted heteroaryldiyl group, such as an optionally substituted pyridinediyl group, in particular a p-pyridinediyl group, especially a pyridine-2,5-diyl group, in which the group R 1 -NH-C (= O) -NH- is adjacent to the nitrogen atom of the pyridyl moiety which is substituted in the 4 or 6 position. Preferred optional substituents include C 1 -C 4 alkyl and C 1 -C 4 alkoxy. carbon atoms, especially methyl and methoxy.

Also preferred are compounds of formula (Ia) wherein L ⁴ is a straight or branched chain alkylene group having 1 to 6 carbon atoms, preferably a straight chain branched alkylene group having 1 to 4 carbon atoms. , such as methylene or ethylene, particularly preferably methylene.

Preferred are compounds of formula (Ia) in which A ³ is a methylene group.

Preferred are compounds of formula (Ia) in which A ³ represents an ethylene group.

Also preferred are compounds of formula (Ia) wherein ^Z3 is CH2.

Preference is also given to compounds of the general formula (Ia) in which R represents a hydrogen atom.

Also preferred are compounds of the above formula (Ia) wherein L ^A represents an optionally substituted alkylene group, in particular an optionally substituted ethylene group or an optionally substituted propylene group, especially an optionally substituted ethylene group substituted with a lower alkyl group, aryl group, heteroaryl group, -N (R ⁸ ) -C (= O) -R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ , -NY ⁴ Y ⁵ or

- [C (= O) -N (R ¹⁰ ) -C (R ⁵ ) (R ¹¹ )] _p -C (= O) -NY ⁴ Y ⁵ or an alkyl group substituted with a carboxy group (or an acidic bioisoster), -ZH, -ZR ³ , -C (= O) -NY ⁴ Y ⁵ or -NY ⁴ Y ⁵ . In a preferred embodiment, L ³ is a group

C — ch ₂ ··

· 0

[in which means:

R ³ is hydrogen or lower alkyl (such as methyl) and R 15 is hydrogen or lower alkyl, or R ³ is hydrogen and R ³ is aryl

OQ, heteroaryl, -N (R 0) -C (= O) -R, -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO 2 -R ⁹ , -NY ⁴ Y ⁵ or - [C (= O) -NCR 4 O) -C (r ⁵ ) (R ¹¹ )] p C (= O) -NY ⁴ Y ⁵ or is an alkyl group substituted with a carboxy group (or an acidic bioisoster) , -ZH, -ZR ³ , -C (= O) -NY ⁴ Y ⁵ or -NY ⁴ Y ⁵ ], and is preferably a group,

JH — CH.

especially the group

CH-CH ₂ - [in which R ⁶ represents a hydrogen atom, a lower alkyl group, an aryl group, a heteroaryl group, an -N (R ⁸ ) -C (= O) -R ⁹ , -N (R ⁸ ) group -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ or -NY ⁴ Y ³ or a carboxy-substituted alkyl group, -OH, -OR ³ or -C = O) -NY ⁴ Y ³ ].

In another preferred embodiment, L ¹ is: Ho-c- _R 15a [wherein:

R ³ represents a hydrogen atom or a lower alkyl group (such as a methyl group), and

R ^3a represents a lower alkyl group, or

. »· ··: ♦: h ₂ —CH—

15a

R ⁵ represents a hydrogen atom and R ^5a represents an aryl group, a heteroaryl group, a -N (R 0) -C (= O) -R, -N (R ⁸ ) -C (= O) -OR ⁹ , - N (R ⁸ ) -SO ₂ -R ⁹ , -NY ⁴ Y ⁵ or - [C (= O) -NR ¹ R) -C (R ⁵ ) (RU)] pC (= O) -NY ⁴ Y ⁵ or is an alkyl group substituted with a carboxy group (or an acidic bioisoster), -ZH, -ZR ³ , -C (= O) -NY ⁴ Y ⁵ or -NY ⁴ Y ⁵ ], and is preferably h ₂ -CH ₂ 15a [wherein R ^5a represents a group -N (R ⁸⁾ -C (= 0) -R ⁹ or

-N (R ⁸ ) -SO ₂ -R ⁹ ].

Also preferred are compounds of formula (Ia) in which Y is carboxy.

Also preferred are compounds of formula (Ia) in which:

R is hydrogen,

R ³ represents a 2-substituted phenyl group [in particular

2-methylphenyl or 2-methoxyphenyl] means a methylene group or an ethylene group,

Ar 1 represents an optionally substituted m-phenylene or p-phenylene group (especially

3-chloro-p-phenylene, 3-methyl-p-phenylene, 3-methoxy-p-phenylene,

3-methylthio-p-phenylene,

3-methylsulphinyl-p-phenylene and 3-methylsulphonyl-p-phenylene) or an optionally substituted p-pyridinediyl group [in particular 4 (or 4).

· ·· ♦ ·· · ·

2H-CH ₂ - group, especially

6) -methyl (or methoxy) -p-pyridine-2,5-diyl], ΐΛ represents a group

CH-CH ₉

R ¹⁵ wherein R ¹⁸ is hydrogen, lower alkyl, aryl, heteroaryl, -N (R ⁸ ) -C (= O) -R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ or -ΝΥΝΥΎΎ or an alkyl group substituted with a carboxy group (or an acidic bioisoster), -OH, -OR ⁸ , -O = -O) -Νγ4γ5, ΐΛ means straight or branched chain alkylene of 1 to 6 carbon atoms, in particular methylene,

Y is carboxy, and is CH ₂ , and the corresponding N-oxides and prodrugs thereof, and pharmaceutically acceptable salts and solvates (such as hydrates) of these compounds, and N-oxides and prodrugs thereof.

Another preferred group of compounds of the present invention are those compounds of formula (Ia), wherein:

R is hydrogen,

R is 2-substituted phenyl [in particular 2-methylphenyl or 2-methoxyphenyl],

A 1 'represents a methylene group or an ethylene group,

Ar 1 represents an optionally substituted m-phenylene or p-phenylene group (especially

3-chloro-p-phenylene, 3-methyl-p-phenylene, 3-methoxy-p-phenylene,

3-methylthio-p-phenylene,

3-methylsulfinyl-p-phenylene and 3-methylsulfonyl-p-phenylene) or optionally substituted p-pyridinediyl group [in particular 4 (or 6) -methyl (or methoxy) -p-pyridine-2,5-diyl] , ΐΛ stands for a group

-CH 2 - CH - especially -CH 2 -CH-

_R 15a _R 15a [in which the group is -N (R ⁸ ) -C (= O) -R ⁹ or

-N (R ⁸ ) -SO ₂ -R ⁹ ] means a straight or branched chain alkylene group having 1 to 6 carbon atoms, in particular a methylene group,

Y is carboxy, and TV is CH ₂ , and the corresponding N-oxides and prodrugs thereof, and pharmaceutically acceptable salts and solvates (such as hydrates) of these compounds, and N-oxides and prodrugs thereof.

Another preferred embodiment of the invention is a group of compounds according to the present compound of formula (1b):

(lb) •

9 9 9 * 9 to 9.

'' Kterém kterém kterém kterém kterém kterém kterém kterém kterém kterém kterém kterém kterém kterém kterém kterém kterém

R ^2, R ^3, L ^2, Y and Z 7 have the same meanings as defined above,

X is NR ⁵ or O,

Z ⁴ is a direct bond, NR ⁵ , O or S (O) _n (wherein R ⁵ and _n have the same meaning as previously defined), and

R represents a hydrogen atom or a substituent of an aryl group, and the corresponding N-oxides and prodrugs thereof, and pharmaceutically acceptable salts and solvates (such as hydrates) of these compounds and N-oxides and prodrugs thereof.

According to the invention, compounds of general formula a (1b) are preferred in which R represents an optionally substituted aryl group, in particular a 2-substituted phenyl group. Preferred optional substituents are lower alkyl groups (such as a methyl group), lower alkoxy groups (such as a methoxy group), halogens (such as a fluorine or chlorine) and a Y 2 Y ² Na group (for example a dimethylamino group). In particular, R 0 represents an ortho-tolyl group.

Also preferred are compounds of formula (1b) wherein Z ⁴ is NH.

Also preferred are compounds of formula (1b) wherein R is hydrogen, halogen (such as chlorine), lower alkyl (such as methyl or ethyl) or lower alkoxy (such as methoxy).

·:

:

♦ ··:

··:

Also preferred are compounds of formula (Ib) wherein L ⁴ is a straight or branched chain alkylene group having 1 to 6 carbon atoms, especially a straight or branched chain alkylene group having 1 to 4 carbon atoms, more preferably methylene. group.

Also preferred according to the present invention are compounds of formula (Ib) wherein A ¹ is methylene.

Also preferred are compounds of formula (Ib) wherein A ¹ is an ethylene group.

Also preferred are compounds of formula (Ib) wherein Z ¹ is CH 2.

Also preferred are compounds of formula (Ib) wherein R is hydrogen.

Also preferred are compounds of the above formula (Ib) wherein L ¹ represents an optionally substituted alkylene group, in particular an optionally substituted ethylene group or an optionally substituted propylene group, especially an optionally substituted ethylene group substituted by lower alkyl, aryl, heteroaryl, -N (R ⁸ ) -C (= O) -R 4, -N (R ⁸ ) -C (= O) -OR 4, -N (R ⁸ ) -SO ₂ -R ⁹ , -NY ⁴ Y ⁵ or

0 · '* • 0 0 0 0 0 • · · · • 0 0 · 0 '0 • · · 0 0 0 · • 0 · · • 0 0 0 0 0 0 * · 0 0 0 0 00 ·· 0 0 ‘0 »0 0 0 ·

- [C (= O) -N (R ¹⁰ ) -C (R ⁵ ) (R ¹¹ )] _p -C (= O) -NY ⁴ Y ⁵ 'or an alkyl group substituted with a carboxy group (or an acidic bioisoster), -ZH , -ZR ³ , -C (= O) -NY ⁴ Y ⁵ or -NY ⁴ Y ⁵ . According to one preferred embodiment, ΐΛ represents the group —c —ch ₂ I

R ¹⁵ [in which:

R @ 1 is hydrogen or lower alkyl (such as methyl);

R ³ is hydrogen or lower alkyl, or R ³ is hydrogen and R ³ is aryl

OQ, heteroaryl, -N (R 0) -C (= O) -R, -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ , -NY ⁴ Y ⁵ or - [C (= O) -N (R ¹¹ ) -C (R ³ ) (R ¹¹ )] p C (= O) -NY ⁴ Y ⁵ or is an alkyl group substituted with carboxy (or acidic bioisoster), -ZH, -ZR ³ , -C (= O) -NY ⁴ Y ⁵ or -NY ⁴ Y ⁵ ], and is preferably -CH-CH ₂ -E ¹⁵ [in which R R ⁶ represents a hydrogen atom, a lower alkyl group, an aryl group, a heteroaryl group, an -N (R ⁸ ) -C (= O) -R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ or -ΝΥ ⁴ γ ⁵ or an alkyl group substituted with a carboxy group, -OH, -OR ³ or -C = O) -NY ⁴ Y ⁴ ].

In another preferred embodiment, ΐΛ is a group: h — ch ₂ -

R = CH.

R5a [in which:

· · · »

R ³ represents a hydrogen atom or a lower alkyl group (such as a methyl group, ar 15 ' represents a lower alkyl group, or R ³ represents a hydrogen atom and R ^3a represents an aryl group, a heteroaryl group, a -N (R 0) - C (= O) -R

-N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ , -NY ⁴ Y ⁵ or

- [C (= O) -N (R ⁶ ) -C (R ³ ) '(r H)] p C (= O) -NY ⁴ Y ⁵ or is an alkyl group substituted by carboxy (or an acidic bioisoster), -ZH, - and preferably is a group

-c (= u) -Mi · i ~ neoo, τ, r 4 τ T

ÍN - I

-CH.

-CH—

R ^15a

-CH ₂ —CH— especially a group, 1.

R ^15a [wherein R ^23a is -N (R ⁸ ) -C (= O) -R ⁹ or -N (R ⁸ ) -SO ₂ -R ⁹ ].

Also preferred are compounds of formula (1b) above wherein Y is carboxy.

Group of general formula

57 may preferably be attached to the ring at the 6-position or at the 5-position or the 6-position in the case where X is NR ³ and R ³ is lower alkyl.

A preferred group of compounds of the present invention are those compounds of formula (Ib) wherein:

-R represents a hydrogen atom, a chlorine atom, a methyl group, an ethyl group or a methoxy group,

R ² .znamená hydrogen,

R ³ represents an optionally substituted aryl group (especially an ortho-tolyl group),

A * represents methylene; a group or an ethylene group,

L ¹ represents a group

_-CH-O - group of-names - _CH-CH? -

I i

R ¹⁵ R ¹⁵ wherein R ¹³ is hydrogen, lower alkyl, aryl, heteroaryl, -N (R ⁸ ) -C (= O) -R ⁹ , -N (R ⁸ ) -C (= O ) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ or -ΝΫ ⁴ γ ⁵ or an alkyl group substituted with a carboxy group (or an acidic bioisoster), -OH, -ZR ³ , -C = O) -NY ⁴ Y ^ or -NY ⁴ Y ⁵ ,

L ⁴ represents a straight-chain or branched alkylene group having 1 to 4 carbon atoms, in particular a methylene group,

X is 0,

Y is carboxy, and is CH ₂ ,

Z ⁴ is NH, O

and a group of formula

is attached to the ring at the 6-position, and the corresponding N-oxides and prodrugs thereof, and pharmaceutically acceptable salts and solvates (such as hydrates) of these compounds and their N-oxides and prodrugs.

A further preferred group of compounds of the present invention are those of the above formula (TM x from Iz + tα-Áni).

-R represents a hydrogen atom, a chlorine atom, a methyl group, an ethyl group or a methoxy group,

R is hydrogen,

R ³ represents an optionally substituted aryl group (especially an ortho-tolyl group), represents a methylene group or an ethylene group, ΐΛ represents a group

-CH ₂ —CH— especially -CH ₂ -CH-

I 1 j ^ 15a pl5 &

[wherein R ^3a represents a group -N (R ⁸⁾ -C (= 0) -R ⁹ or -N (R ⁸⁾ -SO ₂ -R ^9],

L ⁴ represents an alkylene group containing 1 to 4 atoms

straight or branched chain carbon, in particular methylene,

X is O,

Y is carboxy, and Z ³ is CH ₂ ,

Z ⁴ is NH, and a group of formula

is attached to the ring at the 6-position, and the corresponding N-oxides and prodrugs thereof, and pharmaceutically acceptable salts and solvates (such as hydrates) of these compounds and their N-oxides and prodrugs.

Another preferred group of compounds of the present invention are those compounds of formula (Ib) above wherein:

R is hydrogen,

R ³ represents an optionally substituted aryl group (especially an ortho-tolyl group),

A ³ · represents a methylene group or an ethylene group,

L ³ · represents a group

-CH ₂ -CH ₂ - _R 5 especially a group

• ·· 4 4 • 4 • • 4 4 44 • 4 ·· 4 · · · · · • 4 4 4 4 4 4 4 • 4 4 • • 4 4 • · · 44 4 · 4 44 4

wherein R ³ is hydrogen, lower alkyl, aryl, heteroaryl, -N ^(R8) -C (= O) ^-R9, -N ^(R8) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ or -NY ⁴ Y ³ or an alkyl group substituted with a carboxy group (or an acidic bioisoster), -OH, -OR ³ , -C = O) -NY ⁴ Y ^3, or " NY ⁴ Y ⁵

L ⁴ represents a straight-chain or branched alkylene group having 1 to 4 carbon atoms (in particular a methylene group),

X is NR ³ (especially NH),

Y is carboxy, and is CH ₂ ,

Z ⁴ is NH, and a group of formula

is attached to the ring at the 5 or 6 position, and the corresponding N-oxides and prodrugs thereof, and pharmaceutically acceptable salts and solvates (such as hydrates) of these compounds and their N-oxides and prodrugs.

Another preferred group of compounds of the present invention are those compounds of formula (1b), wherein:

O

R is hydrogen,

R ³ 'represents an optionally substituted aryl group

(Especially the ortho-tolyl group),

A ¹ represents a methylene group or an ethylene group,

L ¹ represents a group

-CH ₂ -CH- especially -CH ₂ -CH- ¹¹ 11 j 15a and j 15a [wherein R ^13a is -N (R ⁸ ) -C (= O) -R 4 or

-N (R ⁸ ) -SO ₂ -R ⁹ ],

L ⁴ represents a straight or branched chain alkylene group having 1 to 4 carbon atoms, in particular a methylene group,

X is NR ³ (especially NH),

Y is carboxy, and

Z ¹ is CH ₂ ,

7? is NH, and a group of formula

is attached to the ring at the 5 or 6 position, and the corresponding N-oxides and prodrugs thereof, and pharmaceutically acceptable salts and solvates (such as hydrates) of these compounds and their N-oxides and prodrugs.

Another preferred group of compounds of the present »- ¹ · £ I ~ r invention are compounds of formula (Ic):

(Ic) wherein: Ar ¹ , L ⁴ , A ¹ , R ² , L ¹ , Y and Z ¹ have the same meaning as previously defined, and the corresponding N-oxides and prodrugs thereof, as well as pharmaceutically acceptable salts and solvates (such as hydrates) of these compounds and their N-oxides and prodrugs.

Preferred are compounds of the formula (Ic) in which Ar ^x represents an optionally substituted phenylene group, in particular an optionally substituted m-phenylene or p-phenylene group, according to a particularly preferred embodiment optionally substituted p-phenylene group. Particularly preferred are compounds of formula (Ic) in which Ar ¹ represents a 3-substituted p-phenylene group in which the substituent is located ortho to position the group

Preferred optional substituents include halogens, (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy, (C 1 -C 4) alkylthio, (C 1 -C 4) alkylsulfinyl, (C 1 -C 4) alkylsulfonyl group especially substituents include chloro, methyl, methoxy, methylthio, methylsulfinyl and methylsulfonyl.

Also preferred are compounds of formula (1c) wherein Ar 1 is an optionally substituted heteroaryldiyl group such as an optionally substituted pyridinediyl group, especially a p-pyridinediyl group, particularly pyridine-2,5- a diyl group in which the group

it is located adjacent to the pyridyl nitrogen atom, which group is optionally substituted in the 4 or 6 position. The substituents present may include an alkyl group having 1 to 4 carbon atoms and an alkoxy group having 1 to 4 carbon atoms, in particular: indicate methyl and methoxy.

Also preferred are compounds of formula (1c) above, wherein L ⁴ is a straight or branched alkylene group having 1 to 6 carbon atoms

In particular straight-chain or branched alkylene having 1 to 4 carbon atoms, in particular methylene.

Also preferred according to the present invention are compounds of the above formula (Ic) in which 3 represents a methylene group.

Also preferred according to the invention are compounds of the above formula (Ic) wherein 3 represents an ethylene group.

Also preferred according to the invention are compounds of the above formula (Ic) in which τΤ represents a CH 2 group.

Preference is also given to compounds of the above formula (Ic) in which 2

R is hydrogen.

Also preferred are compounds of formula (Ic) wherein L ¹ represents an optionally substituted alkylene group, especially an optionally substituted ethylene group or an optionally substituted propylene group, especially an ethylene group optionally substituted by a lower alkyl group, an aryl group, a heteroaryl group -N (R ⁸ ) -C (= O) -R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO 2 -R ⁹ , -NY ⁴ Y ⁵ or - [C (= O) -N (R ¹⁰ ) -C (R ⁵ ) (R ¹¹ )] p C (= O) -NY ⁴ Y ⁵ or an alkyl group substituted with a carboxy group (or an acidic bioisoster), -ZH , -ZR ³ , -C (= O) -NY ⁴ Y ³ or -NY ⁴ Y ³ . In one preferred embodiment, iA is a group

• j ·

-c — ch ₂ 15 [in which means:

R ³ is hydrogen or lower alkyl (e.g., methyl group), and

R ³³ is hydrogen or lower alkyl, or R ³ is hydrogen and R ³³ is an aryl group of Q β, heteroaryl, -N (R c) -C (= 0) -R, -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO 2 -R ⁹ , -NY ⁴ Y ⁵ or - [C (= O) -N (R ¹⁰ ) -C (R ⁵ ) ( R ¹¹ )] pC (= O) -NY ⁴ Y ⁵ or is an alkyl group substituted with carboxy (or an acidic bioisoster), -ZH, -ZR ³ , -C (= O) -NY ⁴ Y ⁵ or -NY ⁴ Y ⁵ ], and preferably is h-CH.

especially the group

-CH-CH ₂ - [in which R ³ - is hydrogen, lower alkyl, aryl, heteroaryl,

8 '

-N (R ⁸ ) -C (= O) -R ^y , -N (R 0) -C (= O) -OR *, -N (R 0) -SO ₂ -R ^y or -NY ⁴ Y ³ or an alkyl group substituted with a carboxy group, -OH, -OR ³ or -C = O) -NY ⁴ Y ³ ].

In another preferred embodiment, L ³ is a group

R * - ^CH 2 —C—

15a

F

• · ·: h ₂ —CH—

15a [in which:

R ³ represents a hydrogen atom or a lower alkyl group (such as a methyl group), and

Rl5a _represents a lower alkyl group (e.g. methyl), or

R ³ is hydrogen and R ^3a is aryl, heteroaryl, -N (R) -C (= O) -R, -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO 2 -R ⁹ , -NY ⁴ Y ⁵ or - [C (= O) -N (R ¹⁰ ) -C (R ⁵ ) (R ¹¹ )] p C (= O) -NY ⁴ Y ⁵ or is an alkyl group substituted with a carboxy group (or an acidic bioisoster), -ZH, -ZR ³ , -C (= O) -NY ⁴ Y ⁵ or -NY ⁴ Y ⁵ ], and preferably is --CH ₂ -CH—. , l, '

R ^15a [wherein R ^23a is -N (R ⁸ ) -C (= O) -R ⁹ or -N (R ⁸ ) -SO ₂ -R ⁹ ].

Also preferred are compounds of the above formula (Ic) wherein Y is carboxy.

Also preferred are compounds of the above formula (Ic) wherein:

R represents a hydrogen atom.

A * · represents a methylene group or an ethylene group,

Ar 1 is optionally substituted m-phenylene or p-phenylene (especially 3-chloro-p-phenylene, 3-methyl-p-phenylene, 3-methoxy-p-phenylene,

3-methylthio-p-phenylene,

• * · • • «· * • ♦ . <1 • · • 9 9 • • 9 9 · • 9 • • · · • • '· • ··. ·· · « I · · « •

3-methylsulfinyl-p-phenylene and 3-methylsulfonyl-p-phenylene) or optionally substituted p-pyridinediyl group [in particular 4 (or 6) -methyl (or methoxy) -p-pyridine-2,5-diyl] , ΐΛ stands for a group

--CH — CH2— especially -CH-CH2—

I 1

R ¹⁵ R ¹⁵ in which R ¹¹ represents a hydrogen atom, a methyl group, an aryl group, a heteroaryl group, an -N (R ⁸ ) -C (= O) -R ⁹ , -N (R ⁵ ) -C (= O) ) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ or -NY ⁴ Y ⁵ or a carboxy-substituted alkyl group, -OH, -OR 4 or -C = O) -NY ⁴ Y ⁴ ,

L ⁴ represents a straight-chain or branched alkylene group having 1 to 4 carbon atoms (in particular a methylene group),

Y is carboxy, and zA is CH 2, and the corresponding N-oxides and prodrugs thereof, and pharmaceutically acceptable salts and solvates (such as hydrates) of these compounds, and N-oxides and prodrugs thereof.

A further preferred group of compounds of the present invention is represented by the compounds of formula (Ic), wherein:

R ² represents a hydrogen atom, ·

A ¹ represents a methylene group or an ethylene group,

Ar ¹ represents an optionally substituted m-phenylene or p-phenylene group (especially

Φ »

9 '»·» Φ'

Φ · φφ ·

3-chloro-p-phenylene, 3-methyl-p-phenylene, 3-methoxy-p-phenylene,

3-methylthio-p-phenylene,

3-methylsulfinyl-p-phenylene and 3-methylsulfonyl-p-phenylene) or an optionally substituted p-pyridinediyl group [especially 4 (or 6) -methyl (or methoxy) -p-pyridine-2,5-diyl] ], ΐΛ stands for group

-CH-- particularly _{-CH2 -CH2} -CH if r15u-15a [wherein R ^5a represents a group -N (R ⁸⁾ -C (= 0) -R ⁹ or

-N (R ⁸ ) -SO ₂ -R ⁹ ],

L ⁴ represents a straight-chain or branched (C 1 -C 4) alkylene group (in particular a methylene group),

Y is carboxy, and LO is CH _2, and the corresponding N-oxides and their prodrugs, as well as pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.

Another particular group of compounds of the present invention are compounds of formula (Id):

o (Id) wherein R ³ , A ¹ , R ² , L ¹ Y and Z ^{1 have the} same meaning as previously defined and the corresponding N-oxides and prodrugs thereof, and further pharmaceutically acceptable salts and solvates (such as e.g. hydrates) of these compounds and their N-oxides and prodrugs.

According to the invention, preferred compounds of the above general formula (Id) are those in which R represents an optionally substituted aryl group, in particular an optionally substituted phenyl group. Preferred optionally present substituents include aryloxy, cyano, halogens (such as chloro or fluoro), lower alkoxy (such as methoxy), lower alkyl (such as methyl), nitro and perfluoro-lower-alkyl (such as trifluoromethyl. Particularly preferably R ³ is 2-chlorophenyl,

5-chloro-2-cyanophenyl, 2-chloro-6-methylphenyl, 2,6-dichlorophenyl, 2,6-difluorophenyl, 4-fluoro-2-trifluoromethyl,

2-methyl-4-nitrophenyl,

2-methyl-5-nitrophenyl, 2-nitrophenyl,

3-nitrophenyl and 2-phenoxyphenyl.

Also preferred are compounds of formula (Id) wherein R is optionally substituted heteroaryl, especially isoquinolinyl, isoxazolyl, pyrazolopyrimidinyl, pyridyl, pyrimidinyl, quinolinyl, thiazolyl and triazolyl, wherein: each of these groups may be optionally substituted with one or more aryl group substituents. Preferred optionally

• c 4 ί

«··. Substituents include alkyl-C (= O) -, aryl, cyano, halogens (such as chlorine or fluorine), lower alkoxy (such as methoxy), lower alkyl (such as methyl), lower alkylsulfonyl, lower alkylthio, nitro and perfluoro-lower-alkyl (such as trifluoromethyl). Particularly preferably, R ³ represents quinolin-4-yl, isoquinolin-2-yl, 2,4-pyridin-3-yl,

2,6-dimethyl-4-trifluoromethylpyridin-3-yl,

4-trifluoromethylpyridin-3-yl,

2-phenyl-4-methyl-1,2,3-triazol-5-yl,

3,5-dimethylisoxazol-4-yl,

2,7-dimethylpyrazolo [1,5-a] pyrimidin-6-yl;

2-isopropyl-4-methylthiazol-5-yl and 4-trifluoromethylpyrimidin-5-yl.

Also preferred are compounds of the above formula (Id) wherein R ³ is an arylalkyl group wherein the aryl group is optionally substituted with one or more aryl group substituents (in particular, halogen, hydroxy, or the like may be substituted).

and methoxy). Particularly preferably, R represents an optionally substituted benzyl group, in particular a 4-hydroxybenzyl group,

3-chloro-4-hydroxybenzyl,

3-fluoro-4-hydroxybenzyl and 4-hydroxy-3-methoxybenzyl.

Also preferred are compounds of the above formula (Id) wherein A * is methylene.

Also preferred are compounds of the above formula (Id) wherein A ¹ is an ethylene group.

Also preferred are compounds of formula (Id) wherein Z ¹ is CH ₂ .

Also preferred are compounds of the above formula (Id) wherein R ² is hydrogen.

Also preferred are compounds of formula (Id) wherein L ¹ is an optionally substituted alkylene group, especially an optionally substituted ethylene group or an optionally substituted propylene group, especially an ethylene group optionally substituted with a lower alkyl group (such as methyl (aryl group), aryl, heteroaryl,

-N (R ⁸ ) -C (= O) -R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO 2 -R ⁹ , -ny ⁴ y ^5, or - [C (= O) -N (R ¹⁰ ) -C (R ⁵ ) (R ¹¹ )] p C (= O) -NY ⁴ Y ⁵ or an alkyl group substituted with a carboxy group (or an acidic bioisoster), -ZH, -ZR ³ , -C (= O) -NY ⁴ Y ⁵ or -NY ⁴ Y ⁵ . In one preferred embodiment, L ¹ is a C 1 -C ₂₁ group

R ¹⁵

• í · ^? : i

* It to this • to it [in which means:

R @ ⁵ is hydrogen or lower alkyl (such as methyl);

R ⁵ is hydrogen or lower alkyl, or R ⁵ is hydrogen and R ⁵ is aryl

OQ, heteroaryl, -N (R) -C (= O) -R, -N (R ⁸⁾ -C (= O) -OR ^9, -N (R ⁸⁾ -SO ₂ -R ^9, -NY ⁴ Y ⁵ or - [C (= O) -NR ¹ R) -C (R ⁵ ) (rH)] pC (= O) -NY ⁴ Y ⁵ or is an alkyl group substituted with a carboxy group (or an acidic bioisoster), -ZH, -ZR ³ , -C (= O) -NY ⁴ Y ⁵ or -NY ⁴ Y ⁵ ], and more preferably is a group

_-CH-CH2 - especially - CH-CH ₂ -

Wherein R ¹⁵ is hydrogen, lower alkyl, aryl, heteroaryl, -N (R ⁸ ) -C (= O) -R ⁹ , -N (R ⁸ ) -C ( = O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ or -NY ⁴ Y ⁵ or a carboxy-substituted alkyl group, -OH, -OR ³ or -C = O) -NY ⁴ Y ⁵ ].

In another preferred embodiment L ¹ is a -CH _O -C-

R ^15a [in which:

R ⁵ represents a hydrogen atom or a lower alkyl group (such as a methyl group), and

R ^5a represents a lower alkyl group, or

R? is hydrogen, and R ^^ is aryl ^and

QQ, heteroaryl, -N (R) -C (= O) -R, -N (R ⁸⁾ -C (= O) -OR ^9, -N (R ⁸⁾ -SO ₂ -R ^9, -NY ⁴ Y ⁵ or - [C (= O) -N (r 10) -C (R 6) (rH)] -C (= O) -NY ⁴ Y ⁵ or is an alkyl group substituted with a carboxy group (or an acidic bioisoster) , -ZH, -ZR ³ , -C (= O) -NY ⁴ Y ³ or -NY ⁴ Y ³ ], and more preferably a known group

-CH 2 CH - especially -CH ₂ - CH

R 15a [in which R ¹ → R ^3] represents a group, -N (R ⁸ ) -C (= O) -R ⁹ or -N (R ⁸ ) -SO 2 -R ⁹ ]. t

Also preferred are compounds of formula (Id) wherein Y is carboxy.

Preference is also given to compounds of the general formula (Id) in which:

R ² is hydrogen,

R ³ represents an optionally substituted phenyl group (especially 2-chlorophenyl, 5-chloro-2-cyanophenyl, 2-chloro-6-methylphenyl,

2,6-dichlorophenyl, 2,6-difluorophenyl,

4-fluoro-2-trifluoromethyl,

2-methyl-4-nitrophenyl, 2-methyl-5-nitrophenyl, 2-nitrophenyl, 3-nitrophenyl and 2-phenoxyphenyl), optionally substituted heteroaryl (especially quinolin-4-yl, isoquinolin-2) -yl, 2,4-pyridin-3-yl,

2,6-dimethyl-4-trifluoromethylpyridin-3-yl,

β * 0 · ·

0 '0'

4-trifluoromethylpyridin-3-yl,

2-phenyl-4-methyl-1,2,3-triazol-5-yl,

3,5-dimethoxyisoxazol-4-yl,

2,7-dimethylpyrazolo [1,5-a] pyrimidin-6-yl,

2-isopropyl-4-methylthiazol-5-yl and 4-trifluoromethylpyrimidin-5-yl) or optionally substituted benzyl (especially

4-hydroxybenzyl, 3-chloro-4-hydroxybenzyl, 3-fluoro-4-hydroxybenzyl and 4-hydroxy-3-methoxybenzyl),

A ¹ represents a methylene group or an ethylene group,

L ¹ represents a group

_-CH-CH2 - 'especially -CH-CH ₂ -

R ¹⁵ R ¹⁵ wherein R ¹³ is hydrogen, methyl, aryl, heteroaryl, -N (R ⁸ ) -C (= O) -R ⁹ , -N (R ⁸ ) -C (= O ) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ or -NY ⁴ Y ^5, or an alkyl group substituted with a carboxy group, -OH, -OR ³ or -C = O) -NY ⁴ Y ³ ,

Y is carboxy, and Z ¹ is CH ₂ , and the corresponding N-oxides and prodrugs thereof, and pharmaceutically acceptable salts and solvates (such as hydrates) of these compounds, and N-oxides and prodrugs thereof.

Another preferred group of compounds of the present invention are those compounds of formula (Id) _; in which:

· $ 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4. 4 4. 4 * · ·· 9 .4 4 4

R ² is hydrogen,

R ³ represents an optionally substituted phenyl group (especially a 2-chlorophenyl group,

5-chloro-2-cyanophenyl, 2-chloro-6-methylphenyl, 2,6-dichlorophenyl, 2,6-difluorophenyl, 4-fluoro-2-trifluoromethyl,

2-methyl-4-nitrophenyl,

2-methyl-5-iiitrophenyl, 2-nitrophenyl,

3-nitrophenyl and 2-phenoxyphenyl), optionally substituted heteroaryl (especially quinolin-4-yl, isoquinolin-2-yl,

2,4-pyridin-3-yl,

2,6-dimethyl-4-trifluoromethylpyridin-3-yl,

4-trifluoromethylpyridin-3-yl,

2-phenyl-4-methyl-1,2,3-triazol-5-yl,

3,5-dimethoxyisoxazol-4-yl;

2,7-dimethylpyrazolo [1,5-a] pyrimidin-6-yl, 2-isopropyl-4-methylthiazol-5-yl and 4-trifluoromethylpyrimidin-5-yl) or optionally substituted benzyl (especially

4-hydroxybenzyl, 3-chloro-4-hydroxybenzyl, 3-fluoro-4-hydroxybenzyl and 4-hydroxy-3-methoxybenzyl) is methylene or ethylene, ΐΛ is especially -CH ₂ -CH -

AND

R ^15a [wherein R ^23a is -N (R ⁸ ) -C (= O) -R ⁹ or -N (R ⁸ ) -SO ₂ -R ⁹ ],: h ₂ —CH—

15a * '· ♦ · ♦ ♦ J ♦ · 4 · 4. 4 4 · ··· · · ··· 4 * · t · tt «« ·

Y is carboxy, and is CH2, and the corresponding N-oxides and prodrugs thereof, and pharmaceutically acceptable salts and solvates (such as hydrates) of these compounds and N-oxides and prodrugs thereof.

Preferred compounds of the present invention are those compounds of formulas (Ia), (1b), (Ic) and (Id) as defined above, wherein R ³ is hydrogen.

Preferred compounds of the present invention are also compounds of formulas (Ia), (1b), (Ic) and (Id) as defined above, wherein R ¹³ is lower alkyl (such as methyl, ethyl, propyl, butyl) group).

Preferred compounds of the present invention are also compounds of formulas (Ia), (1b), (Ic) and (Id) as defined above, wherein R ¹³ is an aryl group (such as an optionally substituted phenyl group).

Preferred compounds of the present invention are also compounds of formula (Ia) as defined above,

-1C (1b), (Ic) and (Id), wherein R ^1J is a group

-N (R ⁸ ) -C (= O) -R ⁹ , especially said group in which R ⁸ represents a hydrogen atom or a lower alkyl group (such as a methyl group) and R ⁹ represents a lower alkyl group (such as a methyl group) an aryl group (such as an optionally substituted phenyl group), a heteroaryl group (such as a pyridyl group, an isoxazolyl group, a triazolyl group, a pyrimidinyl group, a thiazolyl group or

77 (4 *, 4 * pyrazolopyrimidinyl, each optionally substituted with one or more aryl substituents), alkyl substituted with alkoxy (such as -CH ₂ -O-CH ₂ -CH ₂ -OCH ₃ ), alkyl a carboxy-substituted group (such as -CH ₂ -CH ₂ -CO ₂ H and -CH ₂ -CH ₂ -CH ₂ -CO ₂ H) or an alkyl group substituted with -NY ⁴ Y ³ (such as an aminomethyl group) and morpholin-1-ylmethyl).

Preferred compounds of the present invention are also compounds of formulas (Ia), (1b), (Ic) and (Id) as defined above, wherein R ¹⁵ is -N (R ⁸ ) -C (= O) -OR ⁹ , in particular said group in which R ⁸ represents a hydrogen atom or a lower alkyl group (such as a methyl group) and R ⁹ represents a lower alkyl group

a group (such as an ethyl group) or an alkyl group substituted with an aryl group (such as a benzyl group).

Preferred compounds of the present invention are also compounds of the formulas (Ia), (1b), (Ic) and (Id) as defined above, wherein R 4 * ³ is -N (R ⁸ ) -C (= O) - SO ² R ⁹ , in particular said group in which R ⁸ represents a hydrogen atom or a lower alkyl group (such as a methyl group) and R ⁹ represents a lower alkyl group (such as a methyl group), an aryl group [such as an optionally substituted phenyl group] or optionally substituted naphthyl (especially dimethylaminonaphth-17-yl)], heteroaryl (such as substituted pyridyl or optionally substituted imidazolyl).

Preferred compounds of the present invention are

Also compounds of the formulas (Ia), (Ib), (Ic) and (Id) as defined above, in which R ³⁵ represents a group -NY ⁴ Y ⁵ , in particular said group in which Y ⁴ and Y ⁵ represent hydrogen atom.

Preferred compounds of the present invention are also compounds of formulas (Ia), (Ib), (Ic), and (Id) as defined above, wherein R ¹⁵ is -NY ⁴ Y ⁵ , especially said group wherein Y ⁴ and Y ⁵ represents a lower alkyl group (such as a propyl group) or an alkyl group substituted with an aryl group (such as a -CH ₂ -Ph or -CH ₂ -CH ₂ -Ph) group.

Preferred compounds of the present invention are also compounds of formulas (Ia), (Ib), (Ic) and (Id) as defined above, wherein R · ¹ · ⁵ represents a group -NY ⁴ Y ⁵ , in particular said group in which Y ⁴ and Y ⁵ represent an alkyl group substituted with an aryl group (such as -CH ₂ -Ph or -CH ₂ CH ₂ ) -Ph).

Preferred compounds of the present invention are also compounds of formulas (Ia), (Ib), (Ic) and (Id) as defined above, wherein R ⁵ is an alkyl substituted by a carboxy group (or an acidic bioisoster), especially a lower alkyl group substituted by a carboxy group. (such as a carboxymethyl group).

Preferred compounds of the present invention are also compounds of formulas (Ia), (Ib), (Ic) and (Id) as defined above, wherein R ¹⁵ is -OH-substituted alkyl, especially -OH-substituted lower alkyl (e.g. hydroxymethyl

0 '0 group).

Preferred compounds of the present invention are also compounds of formulas (Ia), (Ib), (Ic) and (Id) as defined above, wherein R ³ is alkyl substituted by -OR ³ , especially lower alkyl substituted by -OR ³ ( such as methoxymethyl).

Preferred compounds of the present invention are also compounds of the formulas (Ia), (Ih), (Ic) and (Id) as defined above, wherein R ³ is an alkyl group substituted with -C (= O) -NY ⁴ Y ³ , in particular a lower alkyl group substituted with -C (= O) -NY ⁴ Y ³ (such as e.g.

V ~ ^c '

-OR or a group r ~

Me — N-CH—

Particularly preferred compounds of the invention are also compounds of the above defined formulas (Ia), (Ib), (Ic) and (Id) in which R represents ^iJ:

• 4

'· ♦' ^f '4

- 9 ‘·. · ....: · .. ..

© »·« · .. © e X ’*; ’· © © • <<<<<

- 80 Η, —ΝΗ ₂ , —nhch ₂ ch ₂ ch ₃

-jjg — c — CH — CH2 —CO2 H, ΝΗ — C — CH — CH — CH ₂ CO ₃ H, NH C CH ₂ NH ₂

//; ^κ (wherein R represents a hydrogen atom or an aryl substituent), —ch ₃ , —CH ₂ CH ₃ , —ch ₂ ch ₂ ch ₃ , —ch ₂ ch ₂ ch ₂ ch ₃ , —CH ₂ —OH, —CH ₂ -CO ₂ H or -CH ₂ -OMe

Also preferred are compounds of the formulas (Ia), (1b), (Ic) and (Id) as defined above, wherein R ⁵ is a group

-N (R 6) - c (= O) -OR 6, especially said group in which R 6 represents a hydrogen atom or a lower alkyl group (such as a methyl group) and R 6 represents a lower alkyl group (such as a methyl group) ), aryl (such as optionally substituted phenyl), heteroaryl (such as pyridyl, isoxazolyl, triazolyl, pyrimidinyl, thiazolyl or pyrazolopyrimidinyl, each optionally substituted with one or more aryl substituents), alkyl an alkoxy-substituted group (such as -CH ₂ -O-CH ₂ -CH ₂ -OCH ₃ ), an alkyl group substituted with a carboxy group (such as -CH ₂ -CH ₂ -CO ₂ H, and -CH ₂ -CH ₂ -CH ₂ -CO ₂ H) or an alkyl group substituted with -NY ⁴ Y ⁵ (such as aminomethyl and morpholin-1-ylmethyl).

·. T

• · « • · · · ·· • · ··  · ' <· • ···, '· · «. <···· * · • • · · • · • • · · · - ·· · -. · • «·

Particularly preferred compounds of the present invention are those compounds of formulas (Ia), (1b), (Ic) and (Id) as defined above, wherein R ³ is -N (R ⁸ ) -C (= O) -R ⁹ wherein R ⁹ is a substituted phenyl group selected from 2-chlorophenyl, 5-chloro-2-cyanophenyl, 2-chloro-6-methylphenyl, 2,6-dichlorophenyl, 2,6-difluorophenyl ,

4-fluoro-2-trifluoromethyl,

2-methyl-4-nitrophenyl,

2-methyl-5-nitrophenyl, 2-nitrophenyl,

3-nitrophenyl or 2-phenoxyphenyl.

Also particularly preferred compounds of the present invention are those compounds of formulas (Ia), (1b), (Ic) and (Id) as defined above, wherein R ³ is -N (R ⁸ ) -C (= O) -R ⁹ , wherein R ⁹ is an optionally substituted heteroaryl group selected from quinolin-4-yl, isoquinolin-2-yl, 2,4-pyridin-3-yl,

2,6-dimethyl-4-trifluoromethylpyridin-3-yl,

4-trifluoromethylpyridin-3-yl,

2-phenyl-4-methyl-1,2,3-triazol-5-yl,

3,5-dimethylisoxazol-4-yl,

2,7-dimethylpyrazolo [1,5-a] pyrimidin-6-yl, 2-isopropyl-4-methylthiazol-5-yl, and 4-trifluoromethylpyrimidin-5-yl.

Particularly preferred compounds of the present invention are those selected from the linkage of the acyl carbon atom (C *) of one of the residues (A1 to A34) listed in Table 1 below to the nitrogen atom (N *) of one of the aza- bicyclic residues (B1 '&quot;&quot;,&quot; ¹ &quot;&quot;.&quot;.&quot;.&quot; · ·

'. · ··. · (·· ········ ·

... · · · · · · · · · · · · ···. To B6) shown in Table 2, and by attaching a carbon atom (C *) to the phenyl ring of one of the aza-bicyclic radicals (B1 to B6) shown in Table 2. 2, to the carbon atom (C *) of one of the acidic residues (C1 to C59) listed in Table 3 below.

-84Table 1

• ·· • · · ·· '· 9 9 - 99 9 '9' • · • ··· »9 9 999 9 \ 9 · 9 • • · 9 9 9 · • • · · · 9-9 • · 9 · 9 . ·. ·

Al 9 ch ₃ O Η H II A2 9 ch ₃ JJ-H h ₃ c OF C* II 0 Α3 0 U-J ll 9γ o A4 9 S.-O ¢ 9 Ύ Η H 1 ch ₃ ch ₃ \ h ₃ c. Α5 Cl AND O II A6 <f ^H 3 <c * ° V9 La cl ho-9A Α7 ^cl of9 A8 jPt II HIM O Α9 ^ c * A10 (= = \ J J II in HIM O r H, C 9 _ / o 0 II 3 x ^c * All / ^CH 3 A12 r = \ , ch ₃ O in / Π h ₃ c - (N ^. ^H V r ^ ri o II VV ^C ' Γ h ₃ c ν ^ / Ί ^h Ol 0 II _x c * A13 z ^ · A14 r = \ About "CH, γ J in 9 H h ₃ c * ~ c Oo / ^H 3 ^C WHAT 0 II _x c * z ° h ₃ c

Table 1 (continued)

A15 O A16 X Cl at and J ' ^H 3 ^C mi 1 H 0 II .C* A17 / = ⁷ \ A18 F \ \\ / / / = N- XX L Λ h ₃ c at and J * A19 Γ ³ H A20 C* fT X N no ₂ A21 0 II xf A22 CN AND O II Λ X T T 1 N0 ₂ Cl A23 Γ ³ O A24 CF, | ³ 0 || II •C* V. Ί ^ C * ⁵ h ₃ c- / IN Χ A25 Γ ³ 0 A26 CF, 1 0 II \ Y Ν — N / = < Λ her r O

ι <y ..

. 3.¾¾¾¾ ·· • ·

-86 ···· · · ·· · 9 99 ·

9 9 9 9

99

Table 1 (continued)

A27 CH, O (IN A28 F O II _of c * (ΙΊ Mx _cl F A29 W ' A30 •AND 0 AND ^ ch ₃ A31 pr, 'Pf' A32 Pt 0 II /C* ^x cf ₃ A33 CH, I ³ II _m Ax / ^C * A34 ^H 3 <T o 'l o II / ^c * X A35 O II fť

t. ;;

δδ

Table 3 (continued) • · ..

19 1 • 9 ··· • 99 ·· 9

C9 ♦ CH — CH — CO ₂ H 0 CIO ♦ CH — CH — CO.H 1 ²² 0 Target ♦ CH — CH — CO.H 6 02 / ♦CH — CH — CO · ^H / / ^H 2 03 / _from CH - CO ₂ H - C. O 04 / * CH-CH — CO.H 1 ^{2 2} CH ₂ CO ₂ H 05 / * CH — CH — CO.H 1 2 2 06 / ♦ CH — CH — CO ₂ H ^H ° ^C Y ° A ^H 2 ^Cl 2 \_of 07 / ♦ CH — CH — CO.H | 2 2 08 / ♦ CH — CH — CH ₂ —CO ₂ H 0 About me 09 / ♦ CH — CH — CH ₂ —CO ₂ H C20 ♦ CH — CH — CO.H 1 ² OCHMe. NS ^ C21 * CH — CH — CO.H 2 * C22 ♦ CH — CH — CO.H 1 HN. ^ 0 Me / Jv / Cl Yf A ..... U;

4 · 4 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Β · »····

-89Table 3 (continued)

Table 3 (continued)

C33 * CH — CH — CO, H 1 C34 * CH-CH, CO, H 1 ²² HN ^ O (il ^WITH N C35 * CH-CH-CO 3 H C36 * CH — CH — CO, H 1 1 HN. ^ 0 HN ^^ -O x K h ₃ c · ' C37 * CH — CH — CO ₂ H C38 * CH — CH — CO, H 1 HN ^ O from ^N ° C « at 0 C39 * CH-CH-CO 3 H C40 * CH — CH — CO, H 1 1 / ^Ν \ ζ ^ · ^θ Me .IL · .x.0 Me In f Γΐ ^ Ί w »» C41 ‘Fí C42 IN 1? ο * ° lj * ^c v7

Table 3 (continued)

Φ

Table 3 (continued)

Specific compounds invention j sou: A1-B1-C1; A1-B1-C8; A1-B1-C15; A1-B1-C22; ' A1-B1-C29; A1-B1-C2; A1-B1-C9; A1-B1-C16; A1-B1-C23; A1-B1-C30; A1-B1-C3; A1-B1-C10; A1-B1-C17; A1-B1-C24; A1-B1-C31; A1-B1-C4; A1-B1-C1I; A1-B1-C18; A1-B1-C25; A1-B1-C32; A1-BI-C5; A1-B1-C12; ' A1-B1-C19; A1-B1-C26; A1-B1-C33; A1-B1-C6; A1-B1-C13; A1-B1-C20; A1-B1-C27; A1-B1-C34; A1-B1-C7; A1-B1-C14; A1-B1-C21; A1-B1-C28; A1-B1-C35;

-93- • ·· ·· · • · · · · • »· 4 · • ··· 9 9 9 ···· • '· · 4 · · · 999 98 9 9 · · «'·' 9 9 9 9 «· · 9 · 9 9 · • · · 9 A1-B1-C36; A2-B1-C12; A2-B1- C47; A3-B1-C23; A3-B1-C58; A1-B1-C37; A2-B1-C13; A2-B1-C48; A3-B1-C24; A3-B1-C59; A1-B1-C38; A2-B1-C14; A2-B1- C49; A3-B1-C25; A4-B1-C1; A1-B1-C39; A2-B1-C15; A2-B1-C50; A3-B1-C26; A4-B1-C2; A1-B1-C40; A2-B1-C16; A2-B1-C51; A3-B1- C27; A4-B1-C3; A1-B1-C41; A2-B1-C17; A2-B1-C52; A3-B1-C28; A4-B1-C4; A1-B1-C42; A2-B1-C18; A2-B1-C53; A3-B1-C29; A4-B1-C4; A1-B1-C43; A2-B1-C19; A2-B1-CS4; A3-B1-C30; A4-B1-C6; A1-B1-C44; A2-B1-C20; A2-B1-C55; A3-B1-C30; A4-B1-C8; A1-B1-C45; A2-B1-C21; A2-B1-C56; A3-B1-C32; A4-B1-C7; A1-B1-C46; A2-B1-C22; A2-B1-CS7; A3-B1-C33; A4-B1-C9; A1-B1-C47; A2-B1-C23; A2-B1- C58; A3-B1-C34; A4-B1-C10; A1-B1-C48; A2-B1-C24; A2-B1-C59; A3-B1-C35; A4-B1-C12; A1-B1-C49; A2-B1-C25; A3-B1-C1; A3-B1-C36; A4-B1-C12; A1-B1-C50; A2-B1-C26; A3-B1-C2; A3-B1-C37; A4-B1-C14; A1-B1-C51; A2-B1-C27; A3-B1-C3; A3-B1-C38; A4-B1-C14; A1-B1-C52; A2-B1-C28; A3-B1-C4; A3-B1-C39; A4 - B1 - C15; A1-B1-C53; A2-B1-C29; A3-B1-C8; A3-B1-C40; A4 - B1 - C16; A1-B1-C54; A2-B1-C30; A3-B1-C6; A3-B1-C41; A4-B1-C18; A1-B1-C55; A2-B1-C31; A3-B1-C8; A3-B1-C42; A4-B1'C18; A1-B1-C56; A2-B1-C32; A3-B1-C7; A3-B1-C44; A4-B1-C19; A1-B1-C57; A2-B1-C33; A3-B1-C9; A3-B1-C44; A4-B1-C20; A1-B1-C58; A2-B1-C34; A3-B1-C10; A3-B1-C45; A4-B1-C21; A1-B1-C59; A2-B1-C35; A3-B1-C12; A3-B1-C46; A4-B1-C22; A2-B1-C1; A2-B1-C36; A3-B1-C12; A3-B1- C47; A4-B1-C23; A2-B1-C2; A2-B1-C37; A3-B1-C13; A3-B1-C48; A4-B1-C24; A2-B1-C3; A2-B1-C38; A3-B1-C14; A3-B1-C50; A4-B1-C25; A2-B1-C4; A2-B1-C39; A3-B1-C15; A3-B1-C50; A4-B1-C26; A2-B1-C5; A2-B1-C40; A3 - B1 - C16; A3-B1-C51; A4-B1- C27; A2-B1-C6; A2-B1-C41; A3-B1-C17; A3-B1-C52; A4-B1-C28; A2-B1-C7; A2-B1-C42; A3-B1-C18; A3-B1-C53; A4-B1-C29; A2-B1-C8; A2-B1-C43; A3-B1-C19; A3-B1-C54; A4-B1-C30; A2-B1-C9; A2-B1-C44; A3-B1-G20; A3-B1-C55; A4-B1-C30; A2-B1-C10; A2-B1-C45; A3-B1-C21; A3-B1-C55; A4-B1-C33; A2-B1-C11; A2-B1-C46; A3-B1-C22; A3-B1-C57; A4-B1-C33; ,

• · • β • · 1

A4-B1-C33;

A4-B1-C35;

A4-B1-C36;

A4-B1-C37;

A4-B1-C38;

A4-B1-C39;

A4-B1-C40;

A4-B1-C41;

A4-B1-C42;

A4-B1- C43;

A4-B1-C44;

A4-B1-C45;

A4-B1- C46;

A4-B1- C47;

A4-B1- C48;

A4-B1- C49;

A4-B1-C50;

A4-B1-C51;

A4-B1-C52;

A4-B1-C53;

A4-B1-C54;

A4-B1-C55;

A4-B1-C55;

A4 - B1 - C57;

A4-B1- C58;

A4-B1-C59;

A5-B1-C1;

A5-B1-C2;

A5-B1-C3;

A5-B1-C4;

A5-B1-C5;

A5-B1-C6;

A5-B1-C7;

A5-B1-C8;

A5-B1-C9;

A5-B1-C10;

A5-B1-C11;

A5-B1-C12;

A5-B1-C13;

A5-B1-C14;

A5-B1-C15;

A5-B1-C16;

A5-B1-C17;

A5-B1-C18;

A5-B1-C19;

A5-B1-C20;

A5-B1-C21;

A5-B1-C22;

A5-B1-C23;

A5-B1-C24;

A5-B1-C25;

A5-B1-C26;

A5-B1-C27;

A5-B1-C28;

A5-B1-C29;

A5-B1-C30;

A5-B1-C31;

A5-B1-C32;

A5-B1-C33;

A5-B1-C34;

A5-B1-C35;

A5-B1-C36;

A5-B1-C37;

A5-B1-C38;

A5-B1-C39;

A5-B1-C40;

A5-B1-C41;

A5-B1-C42;

A5-B1-C43;

A5-B1-C44;

A5-B1-C45;

A5-B1-C46;

A5-B1- C47;

A5-B1-C48;

A5-B1-C49;

A5-B1-C50;

A5-B1-C51;

A5-B1-C52;

A5-B1-C53;

A5-B1-C54;

A5-B1-C55;

A5-B1-C56;

A5-B1-C57;

A5-B1-C58;

A5-B1-C59;

A6-B1-C1;

A6-B1-C2;

A6-B1-C3;

A6-B1-C4;

A6-B1-C5;

A6-B1-C6;

A6-B1-C8;

A6-B1-C8;

A6-B1-C9;

A6-B1-C10;

A6-B1-C11;

A6-B1-C12;

A6-B1-C13;

A6-B1-C14;

A6-B1-C15;

A6-B1-C16

A6-B1-C17;

A6-B1-C18;

A6-B1-C19;

A6-B1-C20;

A6-B1-C21;

A6-B1-C22;

A6-B1-C23;

A6-B1-C24;

A6-B1-C25

A6-B1-C26;

A6-B1-C27;

A6-B1-C28;

A6-B1-C29;

A6-B1-C30;

A6-B1-C30;

A6-B1-C32;

A6-B1-C33;

A6-B1-C34

A6-B1-C35;

A6-B1-C36;

A6-B1-C37;

A6-B1-C38;

A6-B1-C39;

A6-B1-C40;

A6-B1-C41;

A6-B1-C42;

A6-B1-C43

A6-B1-C44;

A6-B1-C45;

A6-B1-C46;

A6-B1-C47;

A6-B1-C48;

A6-B1-C49

A6-B1-C50;

A6-B1-C51;

A6-B1-C52

A6-B1-C53;

A6-B1-C54

A6-B1-C55

A6-B1-C55;

A6-B1-C57;

A6-B1-C58;

A6-B1-C59;

A7-B1-C1;

A7-B1-C2;

A7-B1-C3;

A7-B1-C4;

A7-B1-C5;

A7-B1-C6;

A7-B1-C7;

A7-B1-C8;

A7-B1-C9;

A7-B1-C10;

A7-B1-C11;

A7-B1-C12;

A7-B1-C13;

A7-B1-C14;

A7-B1-C15;

A7-B1-C16;

A7-B1-C17;

A7-B1-C18;

A7-B1-C19;

A7-B1-C20;

A7-B1-C21;

A7-B1-C22;

A7-B1-C23;

A7-B1-C24;

A7-B1-C25;

A7-B1-C26;

A7-B1-C27;

A7-B1-C28;

A7-B1-C29;

A7-B1-C30;

A7-B1-C31;

.4

, ν. ... * · -95 - • ·· ··. · - :: :: :: ::. • ··· ♦ · · ···· • · · · · • · ·. · · · · · · · ·· '· ····: ·. ·. ·,. · .. / -, ··· - '- - -', '' - • :. :: •! »· · · - /--.<· . · · R · £ r A7-B1-C32; A8-B1-C8; A8-B1-C43; A9-B1-C19; A9-B1-C54; A7-B1-C33; A8-B1-C9; A8-B1-C44; A9-B1-C20; A9-B1-C55; A7-B1-C34; A8-B1-C10; A8-B1-C45; A9-B1-C21; A9-B1-C56; A7-B1-C35; A8-B1-C11; A8-B1-C46; A9-B1-C22; A9-B1-C57; ~ A7-B1-C36; A8-B1-C12; A8-B1-C47; A9-B1-C23; A9-B1-C58; A7-B1-C37; A8-B1-C13; A8-B1-C48; A9-B1-C24; A9-B1-C59; A7-B1-C38; A8-B1-C14; A8-B1-C49; A9-B1-C25; A10-B1-C1; A7-B1-C39; A8-B1-C15; A8-B1-CS0; A9-B1-C26; A10-B1-C2; A7-B1-C40; A8-B1-C16; A8-B1-C51; A9-B1-C27; A10-B1-C3; A7-B1-C41; A8-B1-C17; A8-B1-CS2; A9-B1-C28; A10-B1-C4; A7-B1-C42; A8-B1-C18; A8-B1-C53; A9-B1-C29; A10-B1-C8; A7-B1-C43; A8-B1-C19; A8-B1-C54; A9-B1-C30; A10-B1-C6; A7-B1-C44; A8-B1-C20; A8-B1-C55; A9-B1-C31; A10-B1-C8; A7-B1-C45; A8-B1-C21; A8-B1-C56; A9-B1-C32; A1O-B1-C8; A7-B1-C46; A8-B1-C22; A8-B1-C57; A9-B1-C33; A10-B1-C9; A7-B1-C47; A8-B1-C23; A8-B1-C58; A9-B1-C34; A1O-B1-C1O; A7-B1-C48; A8-B1-C24; A8-B1-C59; A9-B1-C35; A10-B1-C11; A7-B1-C49; A8-B1-C25; A9-B1-C1; A9-B1-C36; A10-B1-Cl2; - A7-B1-C50; A8-B1-C26; A9-B1-C2; A9-B1-C37; A10-B1-C13; A7-B1-C51; A8-BI-C27; A9-B1-C3; A9-B1-C38; A10-B1-C14; • A7-B1-C52; A8-B1-C28; A9-B1-C4; A9-B1-C39; A10 - B1 - C15; A7-B1-C53; A8-B1-C29; A9-B1-C5; A9-B1-C40; A10-B1-C16; A7-B1-C54; A8-B1-C30; A9-B1-C6; A9-B1-C41; A10-B1-C17; A7-B1-C55; A8-B1-C31; A9-B1-C7; A9-B1-C42; A10-B1-C18; A7-B1-C56; A8-B1-C32; A9-B1-C8; A9-B1-C43; A10-B1-C19; A7-B1-C57; A8-B1-C33; A9-B1-C9; A9-B1-C44; A10-B1-C20; - A7-B1-C58; A8-B1-C34; A9-B1-C10; A9-B1-C45; A10-B1-C21; A7-B1-C59; A8-B1-C35; A9-B1-C11; A9-B1-C46; A10-B1-C22; A8-B1-C1; A8-B1-C36; A9-B1-C12; A9-B1-C47; A10-B1-C23; A8-B1-C2; A8-B1-C37; A9-B1-C13; A9-B1-C48; A10-B1-C24; A8-B1-C3; A8-B1-C38; A9-B1-C14; A9-B1-C49; A10-B1-C25; A8-B1-C4; A8-B1-C39; A9-B1-C15; A9-B1-C50; A10-B1-C26; A8-B1-C8; A8-B1-C40; A9-B1-C16; A9-B1-C51; A10 - B1 - C27; A8-B1-C6; A8-B1-C41; A9-B1-C17; A9-B1-C52; A10-B1-C28; ... <A A8-B1-C7; A8-B1-C42; A9-B1-C18; A9-B1-C53; A1O-B1-C29;  -  'V. -: νΤ ... λ7 '^; . , ...,  - A.7Š2Š;

- 96 - ... · · 6 · · • '·' · • ··· · · ···· · · · * • · · · · · · • '· · · • · · ·· · • · · • · · · · A10-B1-C30; A11-B1-C6; A11-B1-C41; A12-B1-C17; A12-B1-C52; A10-B1-C30; A11-B1-C8; A11-B1-C42; A12-B1-C18; A12-B1-C53; A10-B1-C32; A11-B1-C7; A11-BI-C43; A12-B1-C19; A12-B1-C54; A10-B1-C33; A11-B1-C9; A11-B1-C44; A12-B1-C210; A12-B1-C55; ~ A10-B1-C34; A1I-B1-C10; A11-B1-C45; A12-B1-C21; A12-B1-C55; A10 - B1 - C35; A11-B1-C11; A11-B1-C46; A12-B1-C22; A12-B1-C57; A10-B1-C36; A11-B1-C12; A11-B1- C47; A12-B1-C23; A12-B1-C58; A10-B1-C37; A11-B1-C13; A11-B1-C48; A12-B1-C24; A12-B1-C59; A10-B1-C38; A11-B1-C14; A11-B1-C50; A12-B1-C25; A13-B1-C1; A1O-B1'C39; A11-B1-C15; A11-B1-C50; A12-B1-C26; A13-B1-C2; A10-B1-C40; A11 - B1 - C16; A11-B1-C51; A12-B1- C27; A13-B1-C3; A10-B1-C41; A11-B1-C17; A11-B1-C52; A12-B1-C28; A13-B1-C4; A10-B1-C42; A11-B1-C18; A11-B1-C53; A12-B1-C29; A13-B1- C5; A10-B1-C44; A11-B1-C19; A11-B1-C54; A12-B1-C30; A13-B1-C6; A10-B1-C44; A11-B1-C20; A11-B1-C55; A12-B1-C30; A13-B1-C7; A10-B1-C45; A11-B1-C21; A11-B1-C55; A12-B1-C32; A13-B1-C8; A10-B1- C46; A11-B1-C22; A11-B1-C57; A12-B1-C33; A13-B1-C9; A10-B1- C47; A11-B1-C23; A11-B1-C58; A12-B1-C34; A13-B1-C10; A10-B1-C48; A11-B1-C24; A11-B1-C59; A12-B1-C35; A13-B1-C11; A10-B1-C50; A11-B1-C25; A12-B1-C1; A12-B1-C36; A13-B1-C12; A10-B1-C50; A11-B1-C26; A12-B1-C2; A12-B1-C37; A13-B1-C13; A10.B1-C51; A11 - B1 - C27; A12-B1-C3; A12-B1-C38; A13-B1-C14; A10-B1-C52; A11-B1-C28; A12-B1-C4; A12-B1-C39; A13-B1-C15; A10-B1-C53; A11-B1-C29; A12-B1-C4; A12-B1-C40; A13-B1-C16; A10 - B1 - C54; A11-B1-C30; A12-B1-C6; 1212-BI-C41; A13-B1-C17; A10-B1-C55; A11-B1-C30; A12-B1-C8; A12-B1-C42; A13-B1-C18; A10-B1-C55; AX1-B1-C32; A12-B1-C7; A12-B1-C43; A13-B1-C19; A10-B1-C57; A11-B1-C33; A12-B1-C9; A12-B1-C44; A13-B1-C20; A10 - B1 - C58; A11-B1-C34; A12-B1-C10; A12-B1-C45; A13-B1-C21; A10-B1-C59; A11-B1-C35; A12-B1-C11; A12-B1-C46; A13-B1-C22; A11-B1-C1; A11-B1-C36; A12-B1-C12; A12-B1- C47; Al3-B1-C23; A11-B1-C2; A11-B1-C37; A12-B1-C13; A12-B1-C48; A13-B1-C24; A11-B1-C3; A11-B1-C38; A12-B1-C14; A12-B1- C49; A13-B1-C25; A11-B1-C4; A11-B1-C39; A12-B1-C15; A12-B1-C50; A13-B1-C26; A11-B1-C8; A11-B1-C40; A12-B1-C16; A12-B1-C51; A13-B1- C27; and

-97-. '0 · ♦ Η · · · · ·. . . · · . · · · · · • ··· · '· 0 • 0 0 0 · 00 «00 00 0 ·· 0 •. 0 ~ ^ 0. ·; · ·? 0 + - ’♦ ·· 0000 0 0 0 0 ‘0 · 0 0 • ·· 000 A13-B1-C28; A14-B1-C4; A14-B1-C39; A15 - B1 - C15; A1S-B1-C50; A13-B1-C29; A14-B1- C5; A14-B1-C40; A15 - B1 - C16; A15-B1-C51; A13-B1-C30; A14-B1-C6; A14-B1-C41; A15-B1-C17; A1S-B1-C52; A13-B1-C31; A14-B1-C8; A14-B1-C42; A15-B1-C18; A15-B1-C53; A13-B1-C32; A14-B1-C7; A14-B1- C43; A15-B1-C19; A15-B1-C54; A13-B1-C33; A14-B1-C9; A14-B1-C44; A15-B1-C20; A1S-B1-C55; A13-B1-C34; A14-B1-C10; A14-B1-C45; A15-B1-C2I; A1S-B1-C55; A13-B1-C35; A14-B1-C12; A14-B1- C46; A1S-B1-C22; A1S-B1-CS7; A13-B1-C36; A14-B1-C12; A14-B1- C47; A15-B1-C23; A15-B1-C58; A13-B1-C37; A14-B1-C13; A14-B1-C48; A1S-B1-C24; A15-B1-C59; A13-B1-C38; A14-B1-C14; A1-B1-C49; A15-B1-C25; A16-B1-C1; A13-B1-C39; A14-B1- C15; A14-B1-C50; A15-B1-C26; A16-B1-C2; A13-B1-C40; A14-B1- C16; A14-B1-CS1; A15-B1- C27; A16-B1-C3; A13-B1-C41; A14-B1-C17; A14-B1- C52; A15-B1-C28; A16-B1-C4; A13-B1-C42; A14-B1-C18; A14-B1-C53; A15-B1-C29; A16-B1-C4; A13-B1-C43; A14-B1-C19; A14-B1-C54; A15-B1-C30; A16-B1-C6; A13-B1-C44; A14-B1-C20; A14-B1-C55; A15-B1-C30; A16-B1-C8; A13-B1-C45; A14-B1-C21; A14-B1-C55; A15-B1-C32; A16-B1-C8; A13-B1-C46; A14-B1-C22; A14-B1- C57; A15-B1-C33; A16-B1-C9; A13-B1- C47; A14-B1-C23; A14-B1-C58; A15-B1-C34; A16-B1-C10; A13-B1-C48; A14-B1-C24; A14-B1- C59; A15-B1-C35; A16-B1-C12; Al3-B1-C49; A14-B1-C25; A15-B1-C1; A15-B1-C36; A16-B1-C12; A13-B1-C50; A14-BI-C26; A15-B1-C2; A15-B1-C37; A16 - B1 - C13; A13-B1-C51; A14-B1- C27; A15-B1-C3; A15-B1-C38; A16-B1-C14; A13-B1-C52; A14-B1-C28; A15-B1-C4; A15-B1-C39; A16 - B1 - C15; A13-B1-C53; A14-B1-C29; A15-B1-C8; A15-B1-C40; A16 - B1 - C16; A13-B1-C54; A14-B1-C30; A15-B1-C6; A15-B1-C41; A16 - B1 - C17; A13-B1-C55; A14-B1-C30; A15-B1-C8; A15-B1-C42; A16 - B1 - C18; A13-B1-C56; A14-B1-C32; A15-B1-C7; A15-B1- C43; A16-B1-C19; A13-B1-C57; A14-B1-C33; A15-B1-C9; A15-B1-C44; A16-B1-C20; A13-B1-C58; A14-B1-C34; A15-B1-C10; A15-B1-C45; Al6-B1-C2I; A13-B1-C59; A14 - BX - C35; A15-B1-C11; A15-BI-C46; A16-B1-C22; A14-B1-C1; A14-B1-C36; A1S-B1-C12; A15-B1- C47; A16-B1-C23; A14-B1-C2; A14-B1- C37; A15-B1-C13; A15-B1-C48; A16-B1-C24; A14-B1-C3; A14-B1-C38; A15-B1-C14; A15-B1-C50; A16-B1-C25;

98 - 98 - • 4 4. «4 4 · 4 4 4 «< 4 '· · 3 · • 4 4 4 4 • 4 · 4 445 44 «4 Apr '44 · • '4' '· 4. f - • · · · · · · · 4 4 4 · '·· · · • 4-4 · 44 444 A16-B1-C26; A17-B1-C2; A17-B1-C37; A18-BX-C12; A18-B1-C48; A16 - B1 - C27; A17-B1-C3; A17-B1-C38; AX8-BX-C12; A18-B1-C50; A16-B1-C28; A17-B1-C4; A17-B1-C39; A18-B1-C15; A18-B1-C50; A16-B1-C29; A17-B1-C8; A17-B1-C40; A18-BX-CX6; A18.B1-C51; A16-B1-C30; A17-B1-C6; A17-B1-C41; A18-B1-C17; A18-B1-C52; A16-B1> C31; A17-B1-C7; A17-B1-C42; A18-B1-C18; A18-B1-C53; A16 - B1 - C32; A17-B1-C7; A17-B1-C44; A18-B1-C19; A18-B1-C54; A16-B1-C33; Al7-B1-C9; A17-B1-C44; AX8-BX-C20; A18-B1-C55; A16-B1-C34; A17-B1-C10; A17-B1-C45; AX8-B1-C21; A18-B1-C55; A16 - B1 - C35; A17-B1-CII; A17-B1-C46; A18-B1-C22; A18-BX-CS7 A16-B1-C36; A17-B1-C12; A17-B1-C47; A18-B1-C23; A18-B1-C58; A16-B1-C37; A17-B1-C13; A17-B1-C48; AX8-B1-C24; A18 - BX - C59; A16-B1-C38; A17-B1-C14; A17-B1-C49; AX8-BX-C20; A19-B1-C1; A16-B1-C39; A17 - B1 - C15; A17-B1-C50; A18-B1-C26; A19-B1-C2; A16-B1-C40; A17 - B1 - C16; AX7-B1-C5I; AX7-B1-C27; AX9-B1-C3; A16-B1-C41; A17 - B1 - C17; Al7-BX-C52; A18-B1-C28; A19-B1-C4; A16-B1-C42; A17-B1-C18; A17-B1-C53; Al8-B1-C29; A19-BX-C8; A16 - B1 - C43; A17-B1-C19; A17-B1-C54; A18-BI-C30; A19-B1-C6; A16-B1-C44; A17-B1-C20; A17-B1-C55; A18-B1-C30; A19-B1-C8; A16-B1-C45; A17-B1-C21; A17-B1-C55; A18-B1-C32; A19-BI-C8; A16 - B1 - C46; A17-B1-C22; A17-B1-C57; A18-B1-C33; AX9-B1-C8; A16 - B1 - C47; A17-B1-C23; A17-B1-C58; A18-B1-C34; A19-B1-C10; A16-B1-C48; A17-B1-C24; A17-BI-C59; AX7-BX-C35; A19-B1-C12; A16-B1-C50; A17-B1-C25; A18-B1-C1; A18-B1-C36; A19-B1-C12; A16-B1-C50; A17-B1-C26; A18-B1-C2; A18-B1-C37; A19-B1-Cl3; A16-B1-C51; A17 - B1 - C27; AX8-BX-C3; AX8-BX-C38; A19-B1-C14; A16-B1-C52; A17-B1-C28; AX8-BX-C4; A18-B1-C39; , A19-B1-C15; A16-B1-C53; A17-B1-C29; Al8-B1-C5; A18-B1-C40; A19-B1-C16; A16 - B1 - C54; A17-B1-C30; AX8-BX-C6; AX8-B1-C4I; A19-B1-C17; A16-B1-C55; A17-B1-C30; AX8-BX-C8; A18-B1-C42; A19-B1-C18; A16-B1-C55; A17-B1-C32; A18-B1-C8; A18-B1-C44; A19-B1-C19; A16-B1-CS7; A17-B1-C33; A18-B1-C9; A18-B1-C44; A19-B1-C20; A16 - B1 - C58; A17-B1-C34; AX8-B1-C10; A18-B1-C45; AX9-B1-C2X; A16-B1-C59; A17-B1-C35; A18 - BX - CIX; AX7-BX-C46; A19-BX-C22; A17-B1-C1; A17-B1-C36; A18-BX-CX1; AX7-BX-C47; AX9-B1-C23; ... W · *> «- ..« -Ί- ... ; i: - · ®:. · .-. 4 -..... - .......

-99A19-B1-C25;

A19-B1-C25;

A19-B1-C26;

A19-B1- C27;

A19-B1-C28;

A19-B1-C29;

A19-B1-C30;

A19-B1-C30;

A19-B1-C32;

A19-B1-C33;

A19-B1-C34;

A19-B1-C35;

A19-B1-C36;

A19-B1-C37;

A19-B1-C38;

A19-B1-C39;

A19-B1-C40;

A19-B1-C41;

A19-B1-C42;

A19-B1-C44;

A19-B1-C44;

A19-B1-C45;

A19-B1-C46;

A19-B1- C47;

A19-B1-C48;

A19-B1-C50;

A19-B1-C50;

A19-B1-C51;

A19-B1-C52;

A19-BI-C53;

A19-B1-C54;

A19-B1-C55;

A19-B1-C55;

A19-B1-C57;

A19-B1-C58;

A19-B1-C59;

A20-B1-CI;

A20-B1-C2;

A20-B1-C3;

A20-B1-C4;

A20-B1-C8;

A20-B1-C6;

A20-B1-C8;

A20-B1-C7;

A20-B1-C9;

A20-B1-C10;

A20-B1-C12;

A20-B1-C12;

A20-B1-C12;

A20-B1-C14;

A20-B1-C14;

A20-B1-C16;

A20-B1-C16;

A20-B1-C18;

A20-B1-C19;

A20-B1-C20;

A20-B1-C21;

A20-B1-C22;

A20-B1-C23;

A20-B1-C24;

A20-B1-C25;

A20-B1-C26;

A20-B1- C27;

A20-B1-C28;

A20-B1-C29;

A20-B1-C30;

A20-B1-C30;

A20-B1-C30;

A20-B1-C33;

A20-B1-C33;

A20-B1-C35;

A20-B1-C36;

A20-B1-C37;

A20-B1-C38;

A20-B1-C39;

A20-B1-C40;

A20-B1-C41;

A20-B1-C42;

A20-B1-C44;

A20-B1-C44;

A20-B1-C45;

A20-B1-C46;

A20-B1- C47;

A20-B1-C48;

A20-B1-C50;

A20-B1-C50;

A20-B1-C51;

A20-B1-C52;

A20-B1-C53;

A20-B1-C54;

A20-B1-C55;

A20-B1-C55;

A20-B1-C57;

A20-B1-C58;

A20-B1- C59;

A21-B1-C1;

A21-B1-C2;

A21-B1-C3;

A21-B1-C4;

A21-B1-C8;

A21-B1-C6;

A21-B1-C8;

A21-B1-C8;

A21-B1-C9;

A2I-BI-C10;

A21-B1-C11;

A21-B1-C12;

A21-B1-C13;

A21-B1-C14;

A21-B1-C15;

A21-B1-C16;

A21-B1-C17;

A21-B1-C18;

A21-B1-C19;

A21-B1-C20;

A21-B1-C21;

A21-B1-C22;

A21-B1-C23;

A21-B1-C24;

A21-B1-C25;

A21-B1-C26;

A21-B1- C27;

A21-B1-C28;

A21-B1-C29;

A21-B1-C30;

A21-B1-C30;

A21-B1-C32;

A21-B1-C33;

A21-B1-C34;

A21-B1-C35;

A21-B1-C36;

A21-B1-C37;

A21-B1-C38;

A21-B1-C39;

A21-B1-C40;

A21-B1-C41;

A21-B1-C42;

A21-B1-C43;

A21-B1-C44;

A21-B1-C45;

A21-B1-C46;

A21-BI-C47;

A21-B1-C48;

A21-B1-C50;

A21-B1-C50;

A21-B1-C51;

A21-B1-C52;

A21-B1-C53;

A21-B1-C54;

A21-B1-C55;

A21-B1-CS6;

A21-B1-C57;

A21-B1-C58;

A21-B1-C59;

A22-B1-C1;

A22-B1-C2;

A22-B1-C3;

A22-B1-C4;

A22-B1- C5;

A22-B1-C6;

A22-B1-C8;

A22-B1-C8;

A22-B1-C9;

A22-B1-C10;

A22-B1-C12;

A22-B1-C12;

A22-B1-C13;

A22-B1-C14;

A22-B1-C15;

A22-B1-C16;

A22-B1-C17;

A22-B1-C18;

A22-B1-C19;

A22-B1-C20;

A22-B1-C21;

τ '100 · · ·

A22-B1-C22; A22-B1-C57; A23-B1-C33; A24-B1-C9; A24-B1-C44; A22-B1-C23; A22-B1- C58; A23-B1-C34; A24-B1-C10; A24-B1-C45; A22-B1- C24; A22-B1-C59; A23-B1-C35; A24-B1-C12; A24-B1-C46; A22-B1- C25; A23-B1-C1; A23-B1-C36; A24-B1-C11; A24-B1-C47; A22-B1-C26; A23-B1-C2; A23-B1-C37; A24-B1. A24-B1-C48; A22-B1- C27; A23-BI-C3; A23-B1-C38; A24-B1-C14; A24-B1-C49; A22-B1- C28; A23-B1-C4; A23-B1-C39; A24-B1-CI5; A24-B1-C50; A22-B1-C29; A23-B1-C8; A23-B1-C40; A24-B1-C16; A24-B1-C51; A22-B1-C30; A23-B1-C6; A23-B1-C41; A24-B1-C18; A24-B1-CS1; A22-B1- C31; A23-B1-C8; A23-B1-C42; A24-B1-C18; A24-B1-CS2; A22-B1-C32; A23-B1-C8; , A23-B1-C44; A24-B1-C19; A24-B1-C54; A22-B1-C33; A23-B1-C9; A23-B1-C44; A24-B1-C20; A24-B1-C55; A22-B1-C34; A23-B1-C10; A23-B1-C45; A24-B1-C21; A24-B1-C55; A22-B1- C35; A23-B1-CH; A23-B1-C46; A24-B1-C22; A24-B1-C57; A22-B1-C36; A23-B1-C12; A23-B1-C47; A24-B1-C23; A24-B1-C58; A22-B1-C37; A23-B1-C13; A23-B1-C48; A24-B1-C24; A24-B1-C59; A22-B1-C38; A23-B1-C14; A23-B1-C49; A24-B1-C25; A25-B1-C1; A22-B1-C39; A23-B1-C15; A23-B1-C50; A24-B1-C26; A25-BI-C2; A22-B1-C40; A23-B1-C16; A23-B1-C51; A24-B1- C27; A25-B1-C3; A22-B1-C41; A23-B1-C17; A23-B1-C52; A24-B1-C28; A25-BI-C4; A22-B1-C42; A23-B1-C18; A23-B1-C53; A24-B1-C29; A25-B1-C8; A22-B1- C43; A23-B1-C19; A23-B1-C54; A24-B1-C30; A25-B1-C6; A22-B1-C44; A23-B1-C20; A23-B1-C55; A24-B1-C30; A25-B1-C8; A22-B1-C45; A23-B1-C21; A23-B1-C55; A24-B1-C32; A25-B1-C7; A22-B1- C46; A23-B1-C22; A23-B1-C57; A24-B1-C33; A25-B1-C9; A22-B1- C47; A23-B1-C23; A23-B1-C58; A24-B1-C33; A25-B1-C10; A22-B1-C48; A23-B1-C24; A23-B1-C59; A24-B1-C35; A25-B1-C12; A22-B1- C49; A23-B1-C25; A24-B1-C1; A24-B1-C30; A25-B1-C12; A22-B1-C50; A23-B1-C26; A24-B1-C2; A24-B1-C37; A25-B1-C12; A22-B1-C51; A23-B1- C27; A24-B1-C3; A24-B1-C38; A25-B1-C14; A22-B1- C52; A23-B1-C28; A24-B1-C4; A24-B1-C39; A25 - B1 - C15; A22-B1-C53; A23-B1-C29; A24-B1-C8; A24-B1-C40; A25 - B1 - C16; A22-B1-C54; A23-B1-C30; A24-B1-C6; A24-B1-C41; A25-B1-C16; A22-B1-C55; A23-B1-C30; A24-B1-C8; A24-B1-C42; A25-B1-C18; A22-B1-C55; A23-B1-C32; A24-BI-C8; A24-B1-C44; A25-B1-C19; '.

- 7 * ·· +

101 • · ···

A25-BX-C20; A25-BI-C55; A26-BI-C3I; A27-B1-C8; A27-B1-C42; A25-B1-C2I; A25-B1-C55; A26 - B1 - C32; A27-B1-C7; A27-BI-C43; A25-B1-C22; A25-B1-C57; A26 - BX - C33; A27-B1-C9; A27-B1-C44; A25-B1-C23; A25-B1-C58; A26-B1-C33; A27-B1-C10; A27-B1-C45; A25-B1-C24; A25-B1-C59; A26 - B1 - C35; A27-BX-CX2; A27 - B1 - C46; A25-B1-C25; A26-BX-CX; A26-B1-C36; A27-BX-Cl2; A27 - BX - C47; A25-BI-C26; A26-BI-C2; A26-BI-C37; A27-BI-Cl3; A27-B1-C48; A25 - BX - C27; A26-B1-C3; A26-B1-C38; A27-B1-C14; A27-BX-C50; A25 - BX - C28; A26-B1-C4; A26 - BX - C39; A27 - BX - CX5; A27-BI-C50; A25-BX-C30; A26-B1-C8; A26-B1-C40; A27-BI-CX6; A27-B1-C5X; A25-B1-C30; . A26-B1-C6; A26-BX-C4X; A27 - BX - C17; A27 - BX - C52; A25-BX-C3X; A26-B1-C8; A26 - BX - C42; A27 - BX - CX8; A27 - BX - C53; A25-B1-C33; A26-B1-C7; A26-BI-C43 A27-BI-CX9; A27 - BX - C54; A25-B1-C33; A26-B1-C8; A26 - BX - C44; A27-B1-C20; A27 - BX - C55; A25-B1-C33; A26-BX-CX1; A26 - B1 - C45; A27-BX-C2X; A27-BI-C56; A25 - BX - C35; A26-BX-CXX A26-BI-C46; A27-B1-C22; A27 - BX - C57; A25 - BX - C36; A26-B1-C11; A26 - BX - C47; A27 - BX - C23; A27 - BX - C58; A25-B1-C37; A26-B1-CX2; A26-BI-C48; A27-BI-C24; A27 - BX - C59; A25 - BX - C38; A26 - BX - CX4; A26-BI-C49; A27 - B1 - C25; A28-BX-CX; A25-B1-C39; A26-BX-CX4; A26-BX-C50; A27 - BX - C26; A28-BX-C2; A25-B1-C40; A26 - B1 - C16; A26-BX-C5X; A27 - BX - C27; A28-B1-C3; A25-BX-C4X; A26 - B1 - C17; A26 - BX - C52; A27 - BX - C28; A28-BX-C4; A25-B1-C42; A26 - B1 - C18; A26 - BX - C53; A27-BX-C29; A28-B1-C8; A25 - BX - C43; A26-B1-C19; A26-BI-C54; A27 - BX - C30; A28-B1-C6; A25 - BX - C44; A26-BI-C20; A26 - BX - C55; A27-BX-C3X; A28-B1-C8; A25-B1-C45; A26-B1-C21; A26-BX-C55; A27-BX-C33; A28-B1-C7; A25 - B1 - C46; A26-B1-C22; A26 - BX - C57; A27 - BX - C33; A28 - BX - C9; A25 - B1 - C47; A26-B1-C23; A26 - BX - C58; A27-BX-C33; A28-BX-CX1; A25 - BX - C48; A26 - B1 - C24; A26 - BX - C59; A27 - BX - C35; A28-BI-CIX; A25-BI-C49; A26-BI-C25; A27-BX-C1; A27 - BX - C36; A28-BX-CX1; A25-BX-C50; A26-B1-C26; A27-BX-C2; A27 - BX - C37; A28-B1-CX2; A25-B1-C51; A26 - BX - C27; A27-B1-C3; A27-BX-C38; A28-BI-CX5; A25 - BX - C52; A26-B1-C28; A27-BX-C4; A27 - BX - C39; A28-BI-CX4; A25-B1-C53; A26-BX-C29; A27-BX-C8; A27 - BX - C40; A28-BI-CX6; A25 - BX - C54; A26-B1-C30; A27-B1-C6; A27-BX-C4X; A28-B1-C17;

χ7-ί-

- 102- • 44 • · · · · · 4 4 4 4 4 44444 4 4 4 4 4 444 44 44 • 44 .4 • · .4- 4 4 '4 4 4 · 4 “4 ^V 444444 4 4 4 4 4 4 • 44 444 A28 - B1 - C18; A28-B1-C53; A29-BI-C29; A30-B1-C8; A30-B1-C40; A28 - B1 - C19; A28 - B1 - C54; A29-B1-C30; A30-B1-C6; A30-B1-C41; A28-B1-C20; A28-B1-C55; A29-B1-C31; A30-B1-C8; A30 - BX - C42; A28-B1-C21; A28 - B1 - C56; A29-B1-C32; A30-B1-C7; A30-B1-C44; A28-B1-C22; A28 - B1 - C57; A29-B1-C33; A30-B1-C9; A30-B1-C44; A28-B1-C23; A28 - B1 - C58; A29-BX-C34; A30-B1-C10; A30-B1-C45; A28 - B1 - C24; A28-B1-C59; A29-B1-C35; A30-B1-C12; A30-B1-C46; A28 - B1 - C25; A29-B1-C1; A29-B1-C36; A30-B1-C11; A30-B1-C47; A28-B1-C26; A29-B1-C2; A29-B1-C37; A30-B1-C12; A30-B1-C48; A28 - B1 - C27; A29-B1-C3; A29-BX-C38; A30-B1-C14; A30-B1-C50; A28-B1-C28; A29-B1-C4; . A29-B1-C39; A30-BX-C15; A30-BX-C50; A28-B1-C29; A29-B1-C5; A29-B1-C40; A30-B1-C17; A30-B1-C51; A28-B1-C30; A29-B1-C6; A29-B1-C41; A30-B1-C16; A30 - BX - C52; A28-B1-C30; A29-B1-C7; A29-B1-C42; A30-BI-C18; A30-B1-C53; A28 - B1 - C32; A29-B1-C8; A29-B1-C43; A30-BX-C19; A30-B1-C54; A28 - B1 - C33; A29-B1-C9; A29-B1-C44; A30-BX-C20; A30-B1-C55; A28 - B1 - C34; A29-B1-C10; A29-B1-C45; A30-B1-C21; A30-B1-C55; A28 - B1 - C35; A29-B1-C11; A29-B1-C46; A30-B1-C22; A30-B1-C57; A28-B1-C36; A29-B1-C12; A29-BX-C47; A30-B1-C23; A30-B1-C58; A28 - B1 - C37; A29-B1-C13; A29-B1-C48; A30-B1-C24; A30-B1-C59; A28-B1-C38; A29-B1-C14; A29-B1-C49; A30-B1-C25; A31-B1-C1; A28-B1-C39; A29-B1-C15; A29-B1-C50; A30-BX-C25; A31-B1-C2; A28-B1-C40; A29-B1-C16; A29-BI-C5X; A30 - BX - C27; A3X-BI-C3; A28-B1-C41; A29-B1-C17; A29-BX-C52; A30-B1-C28; A3X-BI-C4; A28 - B1 - C42; A29-B1-C18; A29-BX-C53; A30-B1-C29; A31-B1-C8; A28 - B1 - C43; A29-B1-C19; A29-B1-C54; A30-B1-C30; A31-B1-C6; A28-B1-C44; A29-B1-C20; A29-B1-C55; A30-B1-C30; A31-B1-C8; A28 - B1 - C45; A29-B1-C21; A29-BX-C55; A30-B1-C33; A31-B1-C7; A28 - B1 - C46; A29-BX-C22; A29-B1-C57; A30-B1-C33; A31-B1-C9; A28 - B1 - C47; A29-B1-C23; A29-B1-C58; A30-BI-C34; A31-B1-C10; A28-B1-C48; A29-B1-C24; A29-B1-C59; A30-BI-C35; A3X-BI-CXI; A28 - B1 - C49; A29-B1-C25; A30-B1-CX; A30-B1-C36; A31-BX-CX1; A28-B1-C50; A29-B1-C26; A30-B1-C2; A30-B1-C36; A3X-BX-CX2; A28-B1-C51; A29-B1-C27; A30-BX-C3; A30-B1-C38; A3X - BX - CX4; A28-B1-C52; A29-BX-C28; A30-B1-C4; A30-B1-C39; A3X-BI-CX4;

 ί

- - 103 - • * · »» 9 9,999 9 9 9 • · ·. · * »» · · • ·. · '· -, ·· • Φ ··· ······. 9 9 9 · · · • 99,999 A31 - B1 - C16; A31-B1-C51; A32-B1-C28; A33-B1-C3; A33-B1-C38; A31-B1-C17; A31-B1-C52; A32-B1-C28; A33-B1-C4; A33-B1-C39; A31-B1-C18; A31-B1-C53; A32-B1-C29; A33-B1-C8; A33-B1-C40; A31-B1-C19; A31-B1-C54; A32-B1-C30; A33-B1-C6; A33-B1-C41; A31-B1-C20; A31-B1-C55; A32-B1-C30; A33-B1-C8; A33-B1-C42; A31-B1-C21; A31-B1-C55; A32-B1-C32; A33-B1-C7; A33-B1-C44; A31-B1-C22; A31-B1-CS7; A32-B1-C33; A33-B1-C8; A33-B1-C44; A31-B1-C23; A31-B1-C58; A32-B1-C33; A33-B1-C10; A33-B1-C45; A31-B1-C24; A31-B1-C59; A32-B1-C35; A33-B1-C12; A33-B1-C46; A31-B1-C25; A32-B1-C1; A32-B1-C36; A33-B1-C12; A33 - B1 - C47; A31-B1-C20; A32-B1-C2; A32-B1-C36; A33-B1-C12; A33-B1-C48; A31 - B1 - C27; A32-B1-C3; A32-B1-C38; A33-B1-C14; A33-B1-C50; A31-B1-C28; A32-B1-C4; A32-B1-C39; A33-B1-C14; A33-B1-C50; A31-B1-C29; A 32-B1-C5; A32-B1-C40; A33-B1-C17; A33-B1-C51; A31-B1-C30; A32-B1-C6; A32-B1-C41; A33-B1-C16; A33-B1-C52; A31-B1-C31; A32-B1-C8; A32-B1-C41; A33-B1-C18; A33-B1-C53; A31-B1-C32; A32-B1-C7; A32-B1-C44; A33-B1-C19; A33-B1-C54; A31-B1-C33; A32-B1-C9; A32-B1-C44; A33-B1-C20; A33-B1-C55; A31-B1-C34; A32-B1-C10; A32-B1-C45; A33-B1-C21; A33-B1-C55; A31 - B1 - C35; A32-B1-C12; A32-B1-C46; A33-B1-C22; A33-B1-C57; A31-B1-C36; A32-B1-C11; A32-B1-C47; A33-B1-C23; A33-B1-C58; A31-B1-C37; A32-B1-C12; A32-B1-C48; A33-B1-C24; A33-B1-C59; A31-B1-C38; A32-B1-C14; A32-B1-C50; A33-B1-C25; A34-B1-C1; A31-B1-C39; A32-B1-C14; A32-B1-C50; A33-B1-C26; A34-B1-C2; A31-B1-C40; A32-B1-C17; A32-B1-C51; A33-B1-C28; A34-B1-C3; A31-B1-C41; A32-B1-C16; A32-B1-C52; A33-B1-C28; A34-B1-C4; A31-B1-C42; A32-B1-C18; A32-B1-C53; A33-B1-C29; A34-B1-C8; A31 - B1 - C43; A32-B1-C19; A32-B1-C54 A33-B1-C30; A34-B1-C6; A31-B1-C44; A32-B1-C20; A32-B1-C55 A33-B1-C30; A34-B1-C8; A31-B1-C45; A32-B1-C21; A32-B1-C55; A33-B1-C33; A34-B1-C7; A31-B1-C46; A32-B1-C22; A32-B1-C57; A33-B1-C33; A34-B1-C9; A31 - B1 - C47; A32-B1-C22; A32-B1-C58; A33-B1-C33; A34-B1-C10; A31-B1-C48; A32-B1-C24; A32-B1-C59; A33-B1-C35; A34-B1-C12; A31-B1-C49; A32-B1-C25; A33-B1-C1; A33-B1-C36; A34-B1-C12; A31-B1-C50; A32-B1-C25; A33-B1-C2; A33-B1-C37; A34-B1-C12; -

- 104 - '· · • · * · this> • · · · ··· · ··· • -to it · · • · to · •• r · «to · to- to · · · • this · * · A34-BI-C14; A34-B1-C50; A35-B1-C25; A1-B2-Cl; A1-B2-C36; A34-B1-C14; A34-B1-C50; A35-B1-C26; A1-B2-C2; A1-B2-C37; A34-B1-C16; A34-B1-C51; A35-B1- C27; A1-B2-C3; A1-B2-C38; A34-B1-C18; A34-B1-C52; A35-B1-C28; A1-B2-C4; A1-B2-C39; A34-B1-C18; A34-B1-C53; A3S-B1-C30; A1-B2-CS; A1-B2-C40; A34-B1-C19; A34-B1-C54; A35-B1-C30; A1-B2-C6; A1-B2-C41; A34-B1-C20; A34-B1-C55; A35-B1-C30; A1-B2-C7; A1-B2-C42; A34-B1-C21; A34-B1-C55; A3S-B1-C33; A1-B2-C8; A1-B2-C43; A34-B1-C22; A34-B1-C57; A35-B1-C33; A1-B2-C9; A1-B2-C44; A34-B1-C23; A34-B1-C58; A35-B1-C34; A1-B2-C10; A1-B2-C45; A34-B1-C24; A34-B1-C59; A35-B1-C35; A1-B2-C11; A1-B2-C46; A34-B1-C25; A35-B1-C1; A35-B1-C36; A1-B2-C12; A1-B2-C47; A34-B1-C26; A35-B1-C2; A35-B1-C37; A1-B2-C13; A1-B2-C48; A34-B1-C28; A35-B1-C3; A35-B1-C38; A1-B2-C14; A1-B2-C49; A34-B1-C28; A35-B1-C4; A35-B1-C39; A1-B2-C15; A1-B2-C50; A34-B1-C29; A35-B1-C8; A35-B1-C40; A1-B2-C16; A1-B2-C51; A34-B1-C30; A35-B1-C6; A35-B1-C41; A1-B2-C17; A1-B2-C52; A34-B1-C30; A35-B1-C8; A35-B1-C42; A1-B2-C18; A1-B2-C53; A34-B1-C33; A35-B1-C8; A35-B1-C43 A1-B2-C19; A1-B2-C54; A34-B1-C33; A35-B1-C9; A35-B1-C44; A1-B2-C20; A1-B2-C55; A34-B1-C34 A35-B1-C10; A35-B1-C45; A1-B2-C21; A1-B2-C56; A34-B1-C35; A35-B1-C12; A35-B1-C46; A1-B2-C22; A1-B2-C57; A34-B1-C36; A35-B1-C12; A35-B1- C47; A1-B2-C23; A1-B2-C58; A34-B1-C37; A35-B1-C13; A35-B1-C48; A1-B2-C24; A1-B2-CS9; A34-B1-C38; A35-B1-C14; A35-B1-C50; A1-B2-C25; A2-B2-C1; A34-B1-C39; A35-B1-C15; A35-B1-C50; A1-B2-C26; A2-B2-C2; A34-B1-C40; A35-B1-C16; A35-B1-C51; A1-B2-C27; A2-B2-C3; A34-B1-C41; A35-B1-C17; A35-B1-C52; A1-B2-C28; A2-B2-C4; A34-B1-C42; A35-B1-C18; A35-B1-C53; A1-B2-C29; A2-B2-C5; A34-B1-C44; A35-B1-C19; A35-B1-C54; A1-B2-C30; A2-B2-C6; A34-B1-C44; A35-B1-C20; A35-B1-C55; A1-B2-C31; A2-B2-C7; A34-B1-C4S; A35-B1-C21; A35-B1-C55; A1-B2-C32; A2-B2-C8; A34-B1-C46; A35-B1-C22; A35-B1-C57; A1-B2-C33; A2-B2-C9; A34-B1- C47; A35-B1-C23; A35-B1-C58; A1-B2-C34; A2-B2-C10; A34-B1-C48; A35-B1-C24; ..... A35-B1-C59; A1-B2-C35; A2-B2-C11; - * (('γ—

• 9

• 9 9 · · ·. , -105- • .x _t - «. . 9. 9.9 "·. , 'I 999 9 9 9 9999 · • 9 9 9 9 99999 4 · ·

A2-B2-C12;

A2-B2-C13;

A2-B2-C14;

A2-B2-C15;

A2-B2-C16;

A2-B2-C17;

A2-B2-C18;

A2-B2-C19;

A2-B2-C20;

A2-B2-C21;

A2-B2-C22;

A2-B2-C23;

A2-B2-C24;

A2-B2-C25;

A2-B2-C26;

A2-B2-C27;

A2-B2-C28;

A2-B2-C29;

A2-B2-C30;

A2-B2-C31;

A2-B2-C32;

A2-B2-C33;

A2-B2-C34;

A2-B2-C35;

A2-B2-C36;

A2-B2-C37;

A2-B2-C38;

A2-B2-C39;

A2-B2-C40;

A2-B2-C41;

A2-B2-C42;

A2-B2-C43;

A2-B2-C44;

A2-B2-C45;

A2-B2-C46;

A2-B2-C47;

A2-B2-C48;

A2-B2-C49;

A2-B2-C50;

A2-B2-C51;

A2-B2-C52;

A2-B2-C53;

A2-B2-C54;

A2-B2-C55;

A2-B2-C56;

A2-B2-C57;

A2-B2-C58;

A2-B2-C59;

A3-B2-C1;

A3-B2-C2;

A3-B2-C3;

A3-B2-C4;

A3-B2-CS;

A3-B2-C6;

A3-B2-C7;

A3-B2-C8;

A3-B2-C9;

A3-B2-C10;

A3-B2-C11;

A3-B2-C12;

A3-B2-C13;

A3-B2-C14;

A3-B2-C15;

A3-B2-Cl6;

A3-B2-C17;

A3-B2-C18;

A3-B2-C19;

A3-B2-C20;

A3-B2-C21;

A3-B2-C22;

A3-B2-C23;

A3-B2-C24;

A3-B2-C25;

A3-B2-C26;

A3-B2-C27;

A3-B2-C28;

A3-B2-C29;

A3-B2-C30;

A3-B2-C31;

A3-B2-C32;

A3-B2-C33;

A3-B2-C34;

A3-B2-C35;

A3-B2-C36;

A3-B2-C37;

A3-B2-C38;

A3-B2-C39;

A3-B2-C40;

A3-B2-C41;

A3-B2-C42;

A3-B2-C43;

A3-B2-C44;

A3-B2-C45;

A3-B2-C46;

A3-B2-C47;

A3-B2-C48;

A3-B2-C49;

A3-B2-C50;

A3-B2-C51;

A3-B2-C52;

A3-B2-C53;

A3-B2-C54;

A3-B2-C55;

A3-B2-C56;

A3-B2-C57;

A3-B2-C58;

A3-B2-C59;

A4-B2-C1;

A4-B2-C2;

A4-B2-C3;

A4-B2-C4;

A4-B2-C5;

A4-B2-C6;

A4-B2-C7;

A4-B2-C8;

A4-B2-C9;

A4-B2-C10;

A4-B2-C11;

A4-B2-C12;

A4-B2-C13;

A4-B2-C14;

A4-B2-C15;

A4-B2-C16;

A4-B2-C17;

A4-B2-C18;

A4-B2-C19;

A4-B2-C20;

A4-B2-C21;

A4-B2-C22;

A4-B2-C23;

A4-B2-C24;

A4-B2-C25;

A4-B2-C26;

A4-B2-C27;

A4-B2-C28;

A4-B2-C29;

A4-B2-C30;

A4-B2-C31;

A4-B2-C32;

A4-B2-C33;

A4-B2-C34;

A4-B2-C35;

A4-B2-C36;

A4-B2-C37;

A4-B2-C38;

A4-B2-C39;

A4-B2-C40;

A4-B2-C41;

A4-B2-C42;

A4-B2-C43;

A4-B2-C44;

A4-B2-C45;

A4-B2-C46;

A4-B2-C47;

A4-B2-C48;

A4-B2-C49;

A4-B2-C50;

A4-B2-C51;

A4-B2-C52;

A4-B2-C53;

A4-B2-C54;

A4-B2-C55;

A4-B2-C55;

A4-B2-C57;

A4-B2-C58;

A4-B2-C59;

A5-B2-C1;

A5-B2-C2;

A5-B2-C3;

A5-B2-C4;

A5-B2-C5;

A5-B2-C6;

A5-B2-C7;

A5-B2-C8;

A5-B2-C9;

A5-B2-C10; A5-B2-C45; A5-B2-C11; A5-B2-C46; A5-B2-C12; A5-B2-C47; A5-B2-C13; A5-B2-C48; A5-B2-C14; A5-B2-C49; A5-B2-C15; A5-B2-C50; A5-B2-C16; A5-B2-C51; A5-B2-C17; A5-B2-C52; A5-B2-C18; A5-B2-CS3; A5-B2-C19; A5-B2-C54; A5-B2-C20; A5-B2-C55; A5-B2-C21; A5-B2-C56; A5-B2-C22; A5-B2-C57; A5-B2-C23; A5-B2-C58; A5-B2-C24; A5-B2-C59; A5-B2-C25; A6-B2-C1; A5-B2-C26; A6-B2-C2; A5-B2-C27; A6-B2-C3; A5-B2-C28; A6-B2-C4; A5-B2-C29; . A6-B2-C5; A5-B2-C30; A6-B2-C6; A5-B2-C31; . A6-B2-C7; A5-B2-C32; A6-B2-C8; A5-B2-C33; A6-B2-C9; A5-B2-C34; A6-B2-C10; A5-B2-C35; A6-B2-C11; A5-B2-C36; A6-B2-C12; A5-B2-C37; A6-B2-C13; A5-B2-C38; A6-B2-C14; A5-B2-C39; A6-B2-C15; A5-B2-C40; A6-B2-C16; A5-B2-C41; A6-B2-C17; A5-B2-C42; A6-B2-C18; A5-B2-C43; A6-B2-C19; A5-B2-C44; A6-B2-C20;

-106- • • • · · A6-B2-C21; A6-B2-C56; A6-B2-C22; A6-B2-C57; A6-B2-C23; A6-B2-C58; A6-B2-C24; A6-B2-C59; A6-B2-C25; A7-B2-C1; A6-B2-C26; A7-B2-C2; A6-B2-C27; A7-B2-C3; A6-B2-C28; A7-B2-C4; A6-B2-C29; A7-B2-C5; A6-B2-C30; A7-B2-C6; A6-B2-C31; A7-B2-C7; A6-B2-C32; A7-B2-C8; A6-B2-C33; A7-B2-C9; A6-B2-C34; A7-B2-C10; A6-B2-C35; A7-B2-C11; A6-B2-C36; A7-B2-C12; A6-B2-C37; A7-B2-C13; A6-B2-C38; A7-B2-C14; A6-B2-C39; A7-B2-C15; A6-B2-C40; A7-B2-C16; A6-B2-C41; A7-B2-C17; A6-B2-C42; A7-B2-C18; A6-B2-C43; A7-B2-C19; A6-B2-C44; A7-B2-C20; A6-B2-C45; A7-B2-C21; A6-B2-C46; A7-B2-C22; A6-B2-C47; A7-B2-C23; A6-B2-C48; A7-B2-C24; A6-B2-C49; A7-B2-C25; A6-B2-C50; A7-B2-C26; A6-B2-C51; A7-B2-C27; A6-B2-C52; A7-B2-C28; A6-B2-C53; A7-B2-C29; A6-B2-C54; A7-B2-C30; A6-B2-C55; A7-B2-C31;

A7-B2-C32;

A7-B2-C33;

A7-B2-C34;

A7-B2-C35;

A7-B2-C36;

A7-B2-C37;

A7-B2-C38;

A7-B2-C39;

A7-B2-C40;

A7-B2-C41;

A7-B2-C42;

A7-B2-C43;

A7-B2-C44;

A7-B2-C45;

A7-B2-C46;

A7-B2-C47;

A7-B2-C48;

A7-B2-C49;

A7-B2-C50;

A7-B2-C51;

A7-B2-C52;

A7-B2-C53;

A7-B2-C54;

A7-B2-C55;

A7-B2-C56;

A7-B2-C57;

A7-B2-C58;

A7-B2-C59;

A8-B2-C1;

A8-B2-C2;

A8-B2-C3;

A8-B2-C4;

A8-B2-C5;

A8-B2-C6;

A8-B2-C7;

«« * ·: I

1079 '· 9 ‘4 #' · * · 4 '; · Ϊ 1 · -i · ···. · · »» »·» »» - »» »» »» ® ® »® ® ®.....

A8-B2-C8; A8-B2-C43; A9-B2-C19; A9-B2-C54; A10-B2-C30; A8-B2-C9; A8-B2-C44; A9-B2-C20; A9-B2-C55; A10-B2-C31; A8-B2-C10; A8-B2-C45; A9-B2-C21; A9-B2-C56; A10-B2-C32; A8-B2-C11; A8-B2-C46; A9-B2-C22; A9-B2-C57; A10-B2-C33; A8-B2-C12; A8-B2-C47; A9-B2-C23; A9-B2-C58; A10-B2-C34; A8-B2-C13; A8-B2-C48; A9-B2-C24; A9-B2-C59; A10-B2-C35; A8-B2-C14; A8-B2-C49; A9-B2-C25; A10-B2-C1; A10-B2-C36; A8-B2-C15; A8-B2-C50; A9-B2-C26; A10-B2-C2; A10-B2-C37; A8-B2-C16; A8-B2-C51; A9-B2-C27; A10-B2-C3; A10-B2-C38; A8-B2-C17; A8-B2-C52; A9-B2-C28; A10-B2-C4; A10-B2-C39; A8-B2-C18;  A8-B2-C53; A9-B2-C29; A10-B2-C5; A10-B2-C40; A8-B2-C19; A8-B2-C54; A9-B2-C30; A10-B2-C6; A10-B2-C41; A8-B2-C20; A8-B2-C55; A9-B2-C31; A10-B2-C7; A10-B2-C42; A8-B2-C21; A8-B2-C56; A9-B2-C32; A10-B2-C8; A10-B2-C43; A8-B2-C22; A8-B2-C57; A9-B2-C33; A10-B2-C9; A10-B2-C44; A8-B2-C23; A8-B2-C58; A9-B2-C34; A10-B2-C10; A10-B2-C45; A8-B2-C24; A8-B2-C59; A9-B2-C35; A10-B2-C11; A10-B2-C46; A8-B2-C25; A9-B2-C1; A9-B2-C36; A10-B2-C12; A10-B2-C47; A8-B2-C26; A9-B2-C2; A9-B2-C37; A10-B2-C13; A10-B2-C48; A8-B2-C27; A9-B2-C3; A9-B2-C38; A10-B2-C14; A10-B2-C49; A8-B2-C28; A9-B2-C4; A9-B2-C39; A10-B2-C15; A10-B2-C50; A8-B2-C29; A9-B2-C5; A9-B2-C40; A10-B2-C16; A10-B2-C51; A8-B2-C30; A9-B2-C6; A9-B2-C41; A10-B2-C17; A10-B2-C52; A8-B2-C31; A9-B2-C7; A9-B2-C42; A10-B2-C18; A10-B2-G53; A8-B2-C32; A9-B2-C8; A9-B2-C43; A10-B2-C19; A10-B2-C54; A8-B2-C33; A9-B2-C9; A9-B2-C44; A10-B2-C20; A10-B2-C55; A8-B2-C34; A9-B2-C10; A9-B2-C45; A10-B2-C21; A10-B2-C56; A8-B2-C35; A9-B2-C11; A9-B2-C46; A10-B2-C22; A10-B2-C57; A8-B2-C36; A9-B2-C12; A9-B2-C47; A10-B2-C23; A10-B2-C58; A8-B2-C37; A9-B2-C13; A9-B2-C48; A10-B2-C24; A10-B2-C59; A8-B2-C38; A9-B2-C14; A9-B2-C49; A10-B2-C25; AU-B2-C1; A8-B2-C39; A9-B2-C15; A9-B2-C50; A10-B2-C26; A11-B2-C2; A8-B2-C40; A9-B2-C16; A9-B2-C51; A10-B2-C27; A11-B2-C3; A8-B2-C41; A9-B2-C17; A9-B2-C52; A10-B2-C28; A11-B2-C4; A8-B2-C42; A9-B2-C18; A9-B2-C53; A10-B2-C29; A11-B2-C5; Λ í ·

 ·· ...

. <·., ·, ·. · ··

- 107 · »·

A11-B2-C6; A11-B2-C41; A12-B2-C17; A12-B2-C52; A13-B2-C28; A11-B2-C7; A11-B2-C42; A12-B2-C18; A12-B2-C53; A13-B2-C29; A11-B2-C8; A11-B2-C43; A12-B2-C19; A12-B2-C54; A13-B2-C30; A11-B2-C9; A11-B2-C44; A12-B2-C20; A12-B2-C55; A13-B2-C31; A11-B2-C10; A11-B2-C45; A12-B2-C21; A12-B2-C56; A13-B2-C32; A11-B2-C11; A11-B2-C46; A12-B2-C22; A12-B2-CS7; A13-B2-C33; A11-B2-C12; A11-B2-C47; A12-B2-C23; A12-B2-C58; A13-B2-C34; A11-B2-C13; A11-B2-C48; A12-B2-C24; A12-B2-CS9; A13-B2-C35; A11-B2-C14; A11-B2-C49; A12-B2-C25; A13-B2-C1; A13-B2-C36; A11-B2-C15; A11-B2-C50; A12-B2-C26; A13-B2-C2; A13-B2-C37; A11-B2-C16; A11-B2-C51; A12-B2-C27; A13-B2-C3; A13-B2-C38; A11-B2-C17; A11-B2-C52; A12-B2-C28; A 3 -B 2 -C 4; A13-B2-C39; A11-B2-C18; A11-B2-C53; A12-B2-C29; A13-B2-C5; A13-B2-C40; A11-B2-C19; A11-B2-C54; A12-B2-C30; A13-B2-C6; A13-B2-C41; A11-B2-C20; A11-B2-C55; A12-B2-C31; A13-B2-C7; A13-B2-C42; A11-B2-C21; A11-B2-C56; A12-B2-C32; A13-B2-C8; A13-B2-C43; A11-B2-C22; A11-B2-C57; A12-B2-C33; A13-B2-C9; A13-B2-C44; A11-B2-C23; A11-B2-C58; A12-B2-C34; Al3-B2-C10; A13-B2-C45; A11-B2-C24; A11-B2-C59; A12-B2-C35; A13-B2-C11; A13-B2-C46; A11-B2-C25; A12-B2-Cl; A12-B2-C36; A13-B2-C12; A13-B2-C47; A11-B2-C26; A12-B2-C2; A12-B2-C37; A13-B2-C13; A13-B2-C48; A11-B2-C27; A12-B2-C3; A12-B2-C38; A13-B2-C14; A13-B2-C49; A11-B2-C28; A12-B2-C4; A12-B2-C39; A13-B2-C15; A13-B2-C50; A11-B2-C29; A12-B2-C5; A12-B2-C40; A13-B2-C16; A13-B2-C51; A11-B2-C30; A12-B2-C6; A12-B2-C41; A13-B2-C17; A13-B2-C52; A11-B2-C31; A12-B2-C7; A12-B2-C42; A13-B2-C18; A13-B2-C53; A11-B2-C32; A12-B2-C8; A12-B2-C43; A13-B2-C19; A13-B2-C54; A11-B2-C33; A12-B2-C9; A12-B2-C44; A13-B2-C20; A13-B2-C55; A11-B2-C34; A12-B2-C10; A12-B2-C45; A13-B2-C21; A13-B2-C56; A11-B2-C35; A12-B2-C11; A12-B2-C46; A13-B2-C22; A13-B2-C57; A11-B2-C36; A12-B2-C12; A12-B2-C47; A13-B2-C23; A13-B2-C58; A11-B2-C37; A12-B2-C13; A12-B2-C48; A13-B2-C24; A13-B2-C59; A11-B2-C38; A12-B2-C14; A12-B2-C49; A13-B2-C25; A14-B2-C1; A1-B2-C39; A12-B2-C15; A12-B2-C50; A13-B2-C26; A14-B2-C2; A11-B2-C40; A12-B2-C16; A12-B2-CS1; . : . A13-B2-C27; A14-B2-C3;

τα>

AND

..-and-:;-'.-;.··-; : ·

Her- '** ...

A14-B2-C4;

A14-B2-C5;

A14-B2-C6;

A14-B2-C7;

A14-B2-C8;

A14-B2-C9;

A14-B2-C10;

A14-B2-C11;

A14-B2-C12;

A14-B2-C13;

A14-B2-C14;

A14-B2-C15;

A14-B2-C16;

A14-B2-C17;

A14-B2-C18;

A14-B2-C19;

A14-B2-C20;

A14-B2-C21;

A14-B2-C22;

A14-B2-C23;

A14-B2-C24;

A14-B2-C25;

A14-B2-C26;

A14-B2-C27;

A14-B2-C28;

A14-B2-C29;

A14-B2-C30;

A14-B2-C31;

A14-B2-C32;

A14-B2-C33;

A14-B2-C34;

A14-B2-C35;

A14-B2-C36;

A14-B2-C37;

A14-B2-C38;

-109- ·::: • · · · · .. ·· - - - - - - - - - •:: ··; · ·:: ··: -χ » A14-B2-C39; A15-B2-C15; A15-B2-C50; A16-B2-C26; A14-B2-C40; A15-B2-C16; A1S-B2-C51; A16-B2-C27; A14-B2-C41; A15-B2-C17; A15-B2-C52; A16-B2-C28; A14-B2-C42; A15-B2-C18; A15-B2-C53; A16-B2-C29; - A14-B2-C43; A15-B2-C19; A15-B2-C54; A16-B2-C30; A14-B2-C44; A1S-B2-C20; A15-B2-C55; A16-B2-C31; A14-B2-C45; A15-B2-C21; A15-B2-C56; A16-B2-C32; A14-B2-C46; A15-B2-C22; A15-B2-C57; A16-B2-C33; A14-B2-C47; A15-B2-C23; A15-B2-C58; Α16-B2-C34; A14-B2-C48; A15-B2-C24; A15-B2-C59; A16-B2-C35; A14-B2-C49; A15-B2-C25; A16-B2-C1; A16-B2-C36; A14-B2-C50; A15-B2-C26; A16-B2-C2; A16-B2-C37; A14-B2-C51; A15-B2-C27; A16-B2-C3; A16-B2-C38; A14-B2-C52; A15-B2-C28; A16-B2-C4; A16-B2-C39; A14-B2-C53; A15-B2-C29; A16-B2-C5; A16-B2-C40; A14-B2-C54; A15-B2-C30; A16-B2-C6; A16-B2-C41; A14-B2-C5S; A15-B2-C31; A16-B2-C7; A16-B2-C42; A14-B2-C56; A15-B2-C32; A16-B2-C8; A16-B2-C43; A14-B2-C57; A15-B2-C33; A16-B2-C9; A16-B2-C44; A14-B2-C58; A15-B2-C34; A16-B2-C10; A16-B2-C45; A14-B2-C59; A15-B2-C35; A16-B2-C11; A16-B2-C46; A15-B2-C1; A15-B2-C36; A16-B2-C12; A16-B2-C47; A15-B2-C2; A15-B2-C37; A16-B2-C13; A16-B2-C48; A15-B2-C3; A15-B2-C38; A16-B2-C14; A16-B2-C49; A15-B2-C4; A15-B2-C39; A16-B2-C1S; A16-B2-C50; A15-B2-C5; A1S-B2-C40; A16-B2-C16; A16-B2-C51; A15-B2-C6; A1S-B2-C41; A16-B2-C17; A16-B2-C52; A15-B2-C7; A1S-B2-C42; A16-B2-C18; A16-B2-C53; A15-B2-C8; A15-B2-C43; A16-B2-C19; A16-B2-C54; A15-B2-C9; A15-B2-C44; A16-B2-C20; A16-B2-C55; A15-B2-C10; A1S-B2-C45; A16-B2-C21; A16-B2-C56; A15-B2-C11; A15-B2-C46; A16-B2-C22; A16-B2-C57; A15-B2-C12; A15-B2-C47; A16-B2-C23; A16-B2-C58; A1S-B2-C13; A15-B2-C48; Al6-B2-C24; A16-B2-C59; A15-B2-C14; A15-B2-C49; A16-B2-C25; ‘A17-B2-C1;

and ·· ť · · · ... -110- . · * ··· · '·· • - · - - - ··· ·· * · ·. ·

A17-B2-C2; A17-B2-C37; A18-B2-C13; A18-B2-C48; A19-B2-C24; A17-B2-C3; A17-B2-C38; A18-B2-C14; A18-B2-C49; A19-B2-C25; A17-B2-C4; A17-B2-C39; A18-B2-C15; A18-B2-C50; A19-B2-C26; A17-B2-C5; A17-B2-C40; A18-B2-C16; A18-B2-C51; A19-B2-C27; _ A17-B2-C6; A17-B2-C41; A18-B2-C17; A18-B2-C52; A19-B2-C28; A17-B2-C7; A17-B2-C42; A18-B2-C18; A18-B2-CS3; A19-B2-C29; A17-B2-C8; A17-B2-C43; A18-B2-C19; A18-B2-C54; A19-B2-C30; A17-B2-C9; A17-B2-C44; A18-B2-C20; A18-B2-C55; A19-B2-C31; A17-B2-C10; A17-B2-C45; A18-B2-C21; A18-B2-C56; A19-B2-C32; A17-B2-C11; A17-B2-C46; A18-B2-C22; A18-B2-C57; A19-B2-C33; A17-B2-C12; A17-B2-C47; A18-B2-C23; A18-B2-C58; A19-B2-C34; A17-B2-C13; A17-B2-C48; A18-B2-C24; A18-B2-C59; A19-B2-C35; A17-B2-C14; A17-B2-C49; A18-B2-C25; A19-B2-C1; A19-B2-C36; A17-B2-C15; A17-B2-C50; A18-B2-C26; A19-B2-C2; A19-B2-C37; A17-B2-C16; A17-B2-C51; A18-B2-C27; A19-B2-C3; A19-B2-C38; A17-B2-C17; A17-B2-CS2; A18-B2-C28; A19-B2-C4; A19-B2-C39; A17-B2-C18; A17-B2-C53; A18-B2-C29; A19-B2-C5; A19-B2-C40; A17-B2-C19; A17-B2-C54; A18-B2-C30; A19-B2-C6; A19-B2-C41; A17-B2-C20; A17-B2-C55; A18-B2-C31; A19-B2-C7; A19-B2-C42; A17-B2-C21; A17-B2-C56; A18-B2-C32; A19-B2-C8; A19-B2-C43; A17-B2-C22; A17-B2-CS7; A18-B2-C33; A19-B2-C9; A19-B2-C44; A17-B2-C23; A17-B2-C58; A1S-B2-C34; A19-B2-C10; A19-B2-C45; A17-B2-C24; A17-B2-C59; A18-B2-C35; A19-B2-C11; A19-B2-C46; A17-B2-C25; A18-B2-C1; A18-B2-C36; A19-B2-C12; A19-B2-C47; A17-B2-C26; A18-B2-C2; A18-B2-C37; A19-B2-C13; A19-B2-C48; A17-B2-C27; A18-B2-C3; A18-B2-C38; A19-B2-C14; A19-B2-C49; A17-B2-C28; A18-B2-C4; A18-B2-C39; A19-B2-C1S; A19-B2-C50; A17-B2-C29; A18-B2-C5; A18-B2-C40; A19-B2-C16; A19-B2-C51; A17-B2-C30; A18-B2-C6; A18-B2-C41; A19-B2-C17; A19-B2-C52; A17-B2-C31; A18-B2-C7; A18-B2-C42; A19-B2-C18; A19-B2-C53; A17-B2-C32; A18-B2-C8; A18-B2-C43; A19-B2-C19; A19-B2-C54; A17-B2-C33; A18-B2-C9; A18-B2-C44; A19-B2-C20; A19-B2-C5S; A17-B2-C34; A18-B2-C10; A18-B2-C45; A19-B2-C21; A19-B2-C56; A17-B2-C35; A18-B2-C11; A18-B2-C46; A19-B2-C22; A19-B2-C57; A17-B2-C36; A18-B2-C12; A18-B2-C47; . , A19-B2-C23; A19-B2-C58; -, -

ββ ’4

- -111- 4,444 · 4 4 4 4 4 4 4 4,444 · - ^; · '· ♦ ··· 4 4 4 · 4 4' * · ' A19-B2-C59; A20-B2-C35; A21-B2-C11; A21-B2-C46; A22-B2-C22; A20-B2-C1; A20-B2-C36; A21-B2-C12; A21-B2-C47; A22-B2-C23; A20-B2-C2; A20-B2-C37; A21-B2-C13; A21-B2-C48; A22-B2-C24; A20’B2-C3; A20-B2-C38; A21-B2-C14; A21-B2-C49; A22-B2-C25 A20-B2-C4; A20-B2-C39; A21-B2-C15; A21-B2-C50; A22-B2-C26; A20-B2-C5; A20-B2-C40; A21-B2-CR5; A21-B2-C51; A22-B2-C27; A20-B2-C6; A20-B2-C41; A21-B2-C17; A21-B2-C52; A22-B2-C28; A20-B2-C7; A20-B2-C42; A21-B2-C18; A21-B2-C53; A22-B2-C29; A20-B2-C8; A20-B2-C43; A21-B2-C19; A21-B2-C54; A22-B2-C30; A20-B2-C9; A20-B2-C44; A21-B2-C20; A21-B2-C55; A22-B2-C31; A20-B2-C10; A20-B2-C45; A21-B2-C21; A21-B2-C56; A22-B2-C32; A20-B2-C11; A20-B2-C46; A21-B2-C22; A21-B2-C57; A22-B2-C33; A20-B2-C12; A20-B2-C47; A21-B2-C23; A21-B2-C58; A22-B2-C34; A20-B2-C13; A20-B2-C48; A21-B2-C24; A21-B2-C59; A22-B2-C35; A20-B2-C14; A20-B2-C49; A21-B2-C25; A22-B2-C1; A22-B2-C36; A20-B2-C15; A20-B2-C50; A21-B2-C26; A22-B2-C2; A22-B2-C37; A20-B2-C16; A20-B2-C51; A21-B2-C27; A22-B2-C3; A22-B2-C38; A20-B2-C17; A20-B2-C52; A2i-B2-C28; A22-B2-C4; A22-B2-C39; A20-B2-C18; A20-B2-C53; A21-B2-C29; A22-B2-C5; A22-B2-C40; A20-B2-C19; A20-B2-C54; A21-B2-C30; A22-B2-C6; A22-B2-C41; A20-B2-C20; A20-B2-C55; A21-B2-C31; A22-B2-C7; A22-B2-C42; A20-B2-C21; A20-B2-C56; A21-B2-C32; A22-B2-C8; A22-B2-C43; A20-B2-C22; . A20-B2-C57; A21-B2-C33; A22-B2-C9; A22-B2-C44; A20-B2-C23; A20-B2-C58; A21-B2-C34; A22-B2-C10; A22-B2-C45; A20-B2-C24; A20-B2-C59; A21-B2-C35; A22-B2-C11; A22-B2-C46; A20-B2-C25; A21-B2-C1; A21-B2-C36; A22-B2-C12; A22-B2-C47; A20-B2-C26; A21-B2-C2; A21-B2-C37; A22-B2-C13; A22-B2-C48; A20-B2-C27; A21-B2-C3; A21-B2-C38; A22-B2-C14; A22-B2-C49; A20-B2-C28; A21-B2-C4; A21-B2-C39; A22-B2-C15; A22-B2-C50; A20-B2-C29; A21-B2-C5; A21-B2-C40; A22-B2-C16; A22-B2-CS1; A20-B2-C30; A21-B2-C6; A21-B2-C41; A22-B2-C17; A22-B2-C52; A20-B2-C31; A21-B2-C7; A21-B2-C42; A22-B2-C18; A22-B2-C53; A20-B2-C32; A21-B2-C8; A21-B2-C43; A22-B2-C19; A22-B2-C54; A20-B2-C33; A21-B2-C9; A21-B2-C44; A22-B2-C20; A22-B2-C55; A20-B2-C34; A21-B2-C10; A21-B2-C45; A22-B2-C21; A22-B2-C56; * - '· ···' I - * ·

112 • 99

P i '. ·

9 4

9 · • 99 ·

A22-B2-C57;

A22-B2-C58;

A22-B2-C59;

A23-B2-C1;

A23-B2-C2;

A23-B2-C3;

A23-B2-C4;

A23-B2-C5;

A23-B2-C6;

A23-B2-C7;

A23-B2-C8;

A23-B2-C9;

A23-B2-C10;

A23-B2-C11;

A23-B2-C12:

A23-B2-C13;

A23-B2-C14;

A23-B2-C15;

A23-B2-C16;

A23-B2-C17;

A23-B2-C18;

A23-B2-C19;

A23-B2-C20;

A23-B2-C21;

A23-B2-C22;

A23-B2-C23;

A23-B2-C24;

A23-B2-C25;

A23-B2-C26;

A23-B2-C27;

A23-B2-C28;

A23-B2-C29;

A23-B2-C30;

A23-B2-C31;

A23-B2-C32;

A23-B2-C33;

A23-B2-C34;

A23-B2-C35;

A23-B2-C36;

A23-B2-C37;

A23-B2-C38;

A23-B2-C39;

A23-B2-C40;

A23-B2-C41;

A23-B2-C42;

A23-B2-C43;

A23-B2-C44;

A23-B2-C45;

A23-B2-C46;

A23-B2-C47;

A23-B2-C48;

A23-B2-C49;

A23-B2-C50;

A23-B2-C51;

A23-B2-C52;

A23-B2-C53;

A23-B2-C54;

A23-B2-C55;

A23-B2-C56;

A23-B2-C57;

A23-B2-C58;

A23-B2-C59;

A24-B2-C1;

A24-B2-C2;

A24-B2-C3;

A24-B2-C4;

A24-B2-C5;

A24-B2-C6;

A24-B2-C7;

A24-B2-C8;

A24-B2-C9;

A24-B2-C10;

A24-B2-C11;

A24-B2-C12;

A24-B2-C13;

A24-B2-C14;

A24-B2-C15;

A24-B2-C16;

A24-B2-C17;

A24-B2-C18;

A24-B2-C19;

A24-B2-C20;

A24-B2-C21;

A24-B2-C22;

A24-B2-C23;

A24-B2-C24;

A24-B2-C25;

A24-B2-C26;

A24-B2-C27;

A24-B2-C28;

A24-B2-C29;

A24-B2-C30;

A24-B2-C31;

A24-B2-C32;

A24-B2-C33;

A24-B2-C34;

A24-B2-C35;

A24-B2-C36;

A24-B2-C37;

A24-B2-C38;

A24-B2-C39;

A24-B2-C40;

A24-B2-C41;

A24-B2-C42;

A24-B2-C43;

A24-B2-C44;

A24-B2-C45;

A24-B2-C46;

A24-B2-C47;

A24-B2-C48;

A24-B2-C49;

A24-B2-C50;

A24-B2-C51;

A24-B2-C52;

A24-B2-C53;

A24-B2-C54;

A24-B2-C55;

A24-B2-C56;

A24-B2-C57;

A24-B2-C58;

A24-B2-C59;

A25-B2-C1;

A25-B2-C2;

A25-B2-C3;

A25-B2-C4;

A25-B2-C5;

A25-B2-C6;

A25-B2-C7;

A25-B2-C8;

A25-B2-C9;

A25-B2-C10;

A25-B2-C1I;

A25-B2-C12;

A25-B2-C13;

A25-B2-C14;

A25-B2-C15;

A2S-B2-C16;

A2S-B2-C17;

A25-B2-C18;

A25-B2-Cl9;

A25-B2-C20;

A25-B2-C21;

A25-B2-C22;

A25-B2-C23;

A25-B2-C24;

A25-B2-C25;

A25-B2-C26;

A25-B2-C27;

A25-B2-C28;

A25-B2-C29;

A25-B2-C30;

A25-B2-C31;

A25-B2-C32;

A25-B2-C33;

A25-B2-C34;

A25-B2-C35;

A25-B2-C36;

A25-B2-C37;

A25-B2-C38;

A25-B2-C39;

A25-B2-C40;

A25-B2-C41;

A25-B2-C42;

A25-B2-C43;

A25-B2-C44;

A2S-B2-C45;

A25-B2-C46;

A25-B2-C47;

A25-B2-C48;

A25-B2-C49;

A25-B2-C50;

A25-B2-C51;

A25-B2-C52;

A25-B2-C53;

A25-B2-C54;

,, - · -. Ρ μ —Λ. '.

-113-

A25-B2-C55; A26-B2-C31; A27-B2-C7; A25-B2-C56; A26-B2-C32; A27-B2-C8; A25-B2-C57; A26-B2-C33; A27-B2-C9; A25-B2-C58; A26-B2-C34; A27-B2-C10; A25-B2-C59; A26-B2-C35; A27-B2-C11; A26-B2-C1; A26-B2-C36; A27-B2-C12; A26-B2-C2; A26-B2-C37; A27-B2-C13; A26-B2-C3; A26-B2-C38; A27-B2-C14; A26-B2-C4; A26-B2-C39; A27-B2-C15; A26-B2-C5; A26-B2-C40; A27-B2-C16; A26-B2-C6; A26-B2-C41; / A27-B2-Cl7; A26-B2-C7; A26-B2-C42; A27-B2-C18; A26.B2-C8; A26-B2-C43; A27-B2-C19; A26-B2-C9; A26-B2-C44; A27-B2-C20; A26-B2-C10; A26-B2-C45; A27-B2-C21; A26-B2-C11; A26-B2-C46; A27-B2-C22; A26-B2-C12; A26-B2-C47; A27-B2-C23; A26-B2-C13; A26-B2-C48; A27-B2-C24; A26-B2-C14; A26-B2-C49; A27-B2-C25; A26-B2-C15; A26-B2-C50; A27-B2-C26; A26-B2-C16; A26-B2-C51; A27-B2-C27; A26-B2-C17; A26-B2-C52; A27-B2-C28; A26-B2-C18; A26-B2-C53; A27-B2-C29; A26-B2-C19; A26-B2-C54; A27-B2-C30; A26-B2-C20; A26-B2-CS5; A27-B2-C31; A26-B2-C21; A26-B2-C56; A27-B2-C32; A26-B2-C22; A26-B2-C57; A27-B2-C33; A26-B2-C23; A26-B2-C58; A27-B2-C34; A26-B2-C24; A26-B2-C59; A27-B2-C35; A26-B2-C25; A27-B2-C1; A27-B2-C36; A26-B2-C26; A27-B2-C2; A27-B2-C37; A26-B2-C27; A27-B2-C3; A27-B2-C38; A26-B2-C28; A27-B2-C4; A27-B2-C39; A26-B2-C29; A27-B2-C5; A27-B2-C40; A26-B2-C30; A27-B2-C6; A27-B2-C41;

, · * · ·· 0 0 «« ·· * · * ·, ... •. · · · · · · · · · · · · · · 9 · ··· · * · '* ’ <9 · · · · «· · · · · - 0.. . • ί. ·> · · • 9 ·· • 0 0 0 0 0 0 ' * · ··· 'ί.Λ' · ^; A27-B2-C42; A28-B2-C18; A27-B2-C43; A28-B2-C19; A27-B2-C44; A28-B2-C20; A27-B2-C45; A28-B2-C21; - A27-B2-C46; A28-B2-C22; A27-B2-C47; A28-B2-C23; - A27-B2-C48; A28-B2-C24; A27-B2-C49; A28-B2-C25; - A27-B2-C50; A28-B2-C26; A27-B2-C51; A28-B2-C27; A27-B2-C52; A28-B2-C28; A27-B2-C53; A28-B2-C29; A27-B2-C54; A28-B2-C30; A27-B2-C55; A28-B2-C31; > A27-B2-C56; A28-B2-C32; A27-B2-C57; A28-B2-C33; A27-B2-C58; A28-B2-C34; A27-B2-C59; A28-B2-C35; ρ A28-B2-C1; A28-B2-C36; A28-B2-C2; A28-B2-C37; A28-B2-C3; A28-B2-C38; A28-B2-C4; A28-B2-C39; A28-B2-C5; A28-B2-C40; A28-B2-C6; A28-B2-C41; - A28-B2-C7; A28-B2-C42; A28-B2-C8; A28-B2-C43; - A28-B2-C9; A28-B2-C44; A28-B2-C10; A28-B2-C45; A28-B2-C11; A28-B2-C46; * A28-B2-C12; A28-B2-C47; A28-B2-C13; . 2828-B2-C48; A28-B2-C14; A28-B2-C49; A28-B2-C15; 2828-B2-C50; - A28-B2-C16; A28-B2-C51; A28-B2-C17; A28-B2-C52; - «« Μ

• · ··

-114 • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · . .. · · ··· · · ···· · · · · · · · · · · · · · · · · · · · · · · ·

A28-B2-CS3;

A28-B2-CS4;

A28-B2-C55;

A28-B2-C56;

A28-B2-CS7;

A28-B2-C58;

A28-B2-C59;

A29-B2-C1;

A29-B2-C2;

A29-B2-C3;

A29-B2-C4;

A29-B2-C5;

A29-B2-C6;

A29-B2-C7;

A29-B2-C8;

A29-B2-C9;

A29-B2-C10;

A29-B2-Cl1;

A29-B2-C12;

A29-B2-C13;

A29-B2-C14;

A29-B2-C15;

A29-B2-C16;

A29-B2-C17;

A29-B2-C18;

A29-B2-C19;

A29-B2-C20;

A29-B2-C21;

A29-B2-C22;

A29-B2-C23;

A29-B2-C24;

A29-B2-C25;

A29-B2-C26;

A29-B2-C27;

A29-B2-C28;

A29-B2-C29;

A29-B2-C30;

A29-B2-C31;

A29-B2-C32;

A29-B2-C33;

A29-B2-C34;

A29-B2-C35;

A29-B2-C36;

A29-B2-C37;

A29-B2-C38;

A29-B2-C39;

A29-B2-C40;

A29-B2-C41;

A29-B2-C42;

A29-B2-C43;

A29-B2-C44;

A29-B2-C45;

A29-B2-C46;

A29-B2-C47;

A29-B2-C48;

A29-B2-C49;

A29-B2-CS0;

A29-B2-C51;

A29-B2-C52;

A29-B2-C53;

A29-B2-CS4;

A29-B2-C55;

A29-B2-C56;

A29-B2-C57;

A29-B2-C58;

A29-B2-C59;

A30-B2-C1;

A30-B2-C2;

A30-B2-C3;

A30-B2-C4;

A30-B2-C5;

A30-B2-C6;

A30-B2-C7;

A30-B2-C8;

A30-B2-C9;

A30-B2-C10;

A30-B2-C11;

A30-B2-C12;

A30-B2-C13;

A30-B2-C14;

A30-B2-C15;

A30-B2-C16;

A30-B2-C17;

A30-B2-C18;

A30-B2-C19;

A30-B2-C20;

A30-B2-C21;

A30-B2-C22;

A30-B2-C23;

A30-B2-C24;

A30-B2-C25;

A30-B2-C26;

A30-B2-C27;

A30-B2-C28;

A30-B2-C29;

A30-B2-C30;

A30-B2-C31;

A30-B2-C32;

A30-B2-C33;

A30-B2-C34;

A30-B2-C35;

A30-B2-C36;

A30-B2-C37;

A30-B2-C38;

A30-B2-C39;

A30-B2-C40;

A30-B2-C41;

A30-B2-C42;

A30-B2-C43;

A30-B2-C44;

A30-B2-C45;

A30-B2-C46;

A30-B2-C47;

A30-B2-C48;

A30-B2-C49;

A30-B2-C50;

A30-B2-C51;

A30-B2-C52;

A30-B2-C53;

A30-B2-CS4;

A30-B2-C55;

A30-B2-C56;

A30-B2-C57;

A30-B2-C58;

A30-B2-C59;

A31-B2-C1;

A31-B2-C2;

A31-B2-C3;

A31-B2-C4;

A31-B2-C5;

A31-B2-C6;

A31-B2-C7;

A31-B2-C8;

A31-B2-C9;

A31-B2-C10;

A31-B2-C11;

A31-B2-C12;

A31-B2-C13;

A31-B2-C14;

A31-B2-C15;

A31-B2-C16;

A31-B2-C17;

A31-B2-C18;

A31-B2-C19;

A31-B2-C20;

A31-B2-C21;

A31-B2-C22;

A31-B2-C23;

A3I-B2-C24;

A31-B2-C25;

A31-B2-C26;

A31-B2-C27;

A31-B2-C28;

A31-B2-C29;

A31-B2-C30;

A31-B2-C31;

A31-B2-C32;

A31-B2-C33;

A31-B2-C34;

A31-B2-C35;

A31-B2-C36;

A31-B2-C37;

A31-B2-C38;

A31-B2-C39;

A31-B2-C40;

A31-B2-C41;

A31-B2-C42;

A31-B2-C43;

A31-B2-C44;

A31-B2-C45;

A31-B2-C46;

A31-B2-C47;

A31-B2-C48;

3131-B2-C49;

A31-B2-C50;

115k ·· ·· '·' '· ·

A31-B2-C51; A32-B2-C27; A33-B2-C3; A33-B2-C38; A34-B2-C14; A31-B2-C52; A32-B2-C28; A33-B2-C4; A33-B2-C39; A34-B2-C15; A31-B2-C53; A32-B2-C29; A33-B2-C5; A33-B2-C40; A34-B2-C16; A31-B2-C54; A32-B2-C30; A33-B2-C6; A33-B2-C41; A34-B2-C17 A31-B2-C55; A32-B2-C31; A33-B2-C7; A33-B2-C42; A34-B2-C18; A31-B2-C56; , A32-B2-C32; A33-B2-C8; A33-B2-C43; A34-B2-C19; A31-B2-C57; A32-B2-C33; A33-B2-C9; A33-B2-C44; A34-B2-C20; A31-B2-C58; A32-B2-C34; A33-B2-C10; A33-B2-C45; A34-B2-C21; A31-B2-C59; A32-B2-C35; A33-B2-C11; A33-B2-C46; A34-B2-C22; A32-B2-C1; A32-B2-C36; A33-B2-C12; A33-B2-C47; A34-B2-C23; A32-B2-C2; A32-B2-C37; A33-B2-C13; A33-B2-C48; A34-B2-C24; A32-B2-C3; A32-B2-C38; A33-B2-C14; A33-B2-C49; A34-B2-C25; A32-B2-C4; A32-B2-C39; A33-B2-C15; A33-B2-C50; A34-B2-C26; A32-B2-C5; A32-B2-C40; A33-B2-C16; A33-B2-C51; A34-B2-C27; A32-B2-C6; A32-B2-C41; A33-B2-C17; A33-B2-C52; A34-B2-C28; A32-B2-C7; A32-B2-C42; A33-B2-C18; A33-B2-C53; A34-B2-C29; A32-B2-C8; A32-B2-C43; A33-B2-C19; A33-B2-C54; A34-B2-C30; A32-B2-C9; A32-B2-C44; A33-B2-C20; A33-B2-C55; A34-B2-C31; A32-B2-C10; A32-B2-C45; A33-B2-C21; A33-B2-C56; A34-B2-C32; A32-B2-C11; A32-B2-C46; A33-B2-C22; A33-B2-C57; A34-B2-C33; A32-B2-C12; A32-B2-C47; A33-B2-C23; A33-B2-C58; A34-B2-C34; A32-B2-C13; A32-B2-C48; A33-B2-C24; A33-B2-C59; A34-B2-C35; A32-B2-C14; A32-B2-C49; A33-B2-C25; A34-B2-C1; A34-B2-C36; A32-B2-Cl5; A32-B2-C50; A33-B2-C26; A34-B2-C2; A34-B2-C37; A32-B2-C16; A32-B2-C51; A33-B2-C27; A34-B2-C3; 3434-B2-C38; A32-B2-C17; A32-B2-C52; A33-B2-C28; A34-B2-C4; A34-B2-C39; A32-B2-C18; A32-B2-C53; A33-B2-C29; A34-B2-C5; A34-B2-C40; A32-B2-C19; A32-B2-C54; A33-B2-C30; A34-B2-C6; A34-B2-C41; A32-B2-C20; A32-B2-C55; A33-B2-C31; A34-B2-C7; A34-B2-C42; A32-B2-C21; A32-B2-C56; A33-B2-C32; A34-B2-C8; A34-B2-C43; A32-B2-C22; A32-B2-C57; A33-B2-C33; A34-B2-C9; A34-B2-C44; A32-B2-C23; A32-B2-CS8; A33-B2-C34; A34-B2-C10; 3434-B2-C45; A32-B2-C24; A32-B2-C59; A33-B2-C35; A34-B2-C11; A34-B2-C46; A32-B2-C25; A33-B2-C1; A33-B2-C36; A34-B2-C12; A34-B2-C47; A32-B2-C26; A33-B2-C2; A33-B2-C37; A34-B2-C13; A34-B2-C48;

116

444 4 ’· 4 4444 '4 4 4 · 4» 44 «4 44 4

A34-B2-C49;

A34-B2-C50;

A34-B2-C51;

A34-B2-C52;

A34-B2-C53;

A34-B2-C54;

A34-B2-C55;

A34-B2-C56;

A34-B2-C57;

A34-B2-C58;

A34-B2-C59;

A35-B2-C1;

A35-B2-C2;

A35'B2-C3;

A35-B2-C4;

A35-B2-C5;

A35-B2-C6;

A35-B2-C7;

A35-B2-C8;

A35-B2-C9;

A35-B2-C10;

A35-B2-C11;

A35-B2-C12;

A35-B2-C13;

A35-B2-C14;

A35-B2-C15;

A35-B2-C16;

A35-B2-C17;

A35-B2-C18;

A35-B2-C19;

A35-B2-C20;

A35-B2-C21;

A35-B2-C22;

A35-B2-C23;

A35-B2-C24;

A35-B2-C25;

A35-B2-C26;

A35-B2-C27;

A35-B2-C28;

A35-B2-C29;

A35-B2-C30;

A35-B2-C31;

A35-B2-C32;

A35-B2-C33;

A35-B2-C34;

A35-B2-C35;

A35-B2-C36;

A3S-B2-C37;

A35-B2-C38;

A35-B2-C39;

A35-B2-C40;

A35-B2-C41;

A35-B2-C42;

A35-B2-C43;

A35-B2-C44;

A35-B2-C45;

A35-B2-C46;

A35-B2-C47;

A35-B2-C48;

A35-B2-C49;

A35-B2-C50;

A35-B2-C51;

A35-B2-C52;

A35-B2-C53;

A35-B2-C54;

A35-B2-C55;

A35-B2-C56;

A35-B2-C57;

A35-B2-C5S;

A35-B2-C59;

A1-B3-C1;

A1-B3-C2;

A1-B3-C3;

A1-B3-C4;

A1-B3-C5;

A1-B3-C6;

A1-B3-C7;

A1-B3-C8;

A1-B3-C9;

A1-B3-C10;

A1-B3-C11;

A1-B3-C12;

A1-B3-Cl3;

A1-B3-C14;

A1-B3-C15;

A1-B3-C16;

A1-B3-C17;

A1-B3-C18;

A1-B3-C19;

A1-B3-C20;

A1-B3-C21;

A1-B3-C22;

A1-B3-C23;

A1-B3-C24;

A1-B3-C25;

A1-B3-C26;

A1-B3-C27;

A1-B3-C28;

A1-B3-C29;

A1-B3-C30;

A1-B3-C31;

A1-B3-C32;

A1-B3-C33;

A1-B3-C34;

A1-B3-C35;

A1-B3-C36; A1-B3-C37; A1-B3-C38; A1-B3-C39; A1-B3-C40; A1-B3-C41; A1-B3-C42; A1-B3-C43; A1-B3-C44; A1-B3-C4S; A1-B3-C46; A1-B3-C47; A1-B3-C48; A1-B3-C49; A1-B3-C50; A1-B3-C51; A1-B3-C52; A1-B3-C53; A1-B3-C54; A1-B3-C55;

A1-B3-C56;

A1-B3-C57;

A1-B3-C58;

A1-B3-C59;

A2-B3-C1;

A2-B3-C2;

A2-B3-C3;

A2-B3-C4;

A2-B 3 -C 5;

A2-B3-C6;

A2-B3-C7;

A2-B3-C8;

A2-B3-C9;

A2-B3-C10;

A2-B3-C11;

A2-B3-C12;

A2-B3-C13;

A2-B3-C14;

A2-B3-C15;

A2-B3-C16;

A2-B3-C17;

A2-B3-C18;

A2-B3-C19;

A2-B3-C20;

A2-B3-C21;

A2-B3-C22;

A2-B3-C23;

A2-B3-C24;

A2-B3-C25;

A2-B3-C26;

A2-B3-C27;

A2-B3-C28;

A2-B3-C29;

A2-B3-C30;

A2-B3-C31;

A2-B3-C32;

A2-B3-C33;

A2-B3-C34;

A2-B3-C35;

A2-B3-C36;

A2-B3-C37;

A2-B3-C38;

A2-B3-C39;

A2-B3-C40;

A2-B3-C41;

A2-B3-C42;

A2-B3-C43;

A2-B3-C44;

A2-B3-C45;

A2-B3-C46;

Τ'Λ ¹ 'ø - V

A2-B3-C47;

A2-B3-C48;

A2-B3-C49;

A2-B3-C50;

A2-B3-C51;

A2-B3-CS2;

A2-B3-C53;

A2-B3-C54;

A2-B3-C55;

A2-B3-C56;

A2-B3-C57;

A2-B3-C58;

A2-B3-C59;

A3-B3-C1;

A3-B3-C2;

A3-B3-C3;

A3-B3-C4;

A3-B 3 -C 5;

A3-B3-C6;

A3-B3-C7;

A3-B3-C8;

A3-B3-C9;

A3-B3-C10;

A3-B3-C11;

A3-B3-C12;

A3-B3-C13;

A3-B3-C14;

A3-B3-C15;

A3-B3-C16;

A3-B3-C17;

A3-B3-C18;

A3-B3-C19;

A3-B3-C20;

A3-B3-C21;

A3-B3-C22;

-117 - . . and • ··· • · • · · e · •. ... ^e ·> · - - - - - - - - - - - - - € € € € € € € € € € € A3-B3-C23; A3-B3-C58; A4-B3-C34; A5-B3-C10; A3-B3-C24; A3-B3-C59; A4-B3-C35; AS-B3-C11; A3-B3-C25; A4-B3-C1; A4-B3-C36; A5-B3-C12; A3-B3-C26; A4-B3-C2; A4-B3-C37; AS-B3-C13; _ A3-B3-C27; A4-B3-C3; A4-B3-C38; A5-B3-C14; A3-B3-C28; A4-B3-C4; A4-B3-C39; A5-B3-C15; A3-B3-C29; A4-B3-C5; A4-B3-C40; A5-B3-C16; A3-B3-C30; A4-B 3 -C 6; A4-B3-C41; A5-B3-C17; A3-B3-C31; A4-B3-C7; A4-B3-C42; A5-B3-C18; A3-B3-C32; A4-B3-C8; A4-B3-C43; A5-B3-C19; A3-B3-C33; A4-B3-C9; A4-B3-C44; A5-B3-C20; A3-B3-C34; A4-B3-C10; A4-B3-C45; A5-B3-C21; A3-B3-C35; _A4-B3: C11; A4-B3-C46; A5-B3-C22; A3-B3-C36; A4-B3-C12; A4-B3-C47; A5-B3-C23; A3-B3-C37; A4-B3-C13; A4-B3-C48; A5-B3-C24; A3-B3-C38; A4-B3-C14; A4-B3-C49; A5-B3-C25; A3-B3-C39; A4-B3-C15; A4-B3-C50; A5-B3-C26; A3-B3-C40; A4-B3-C16; A4-B3-C51; A5-B3-C27; A3-B3-C41; A4-B3-C17; A4-B3-C52; A5-B3-C28; A3-B3-C42; A4-B3-C18; A4-B3-C53; A5-B3-C29; A3-B3-C43; A4-B3-C19; A4-B3-C54; A5-B3-C30; A3-B3-C44; A4-B3-C20; A4-B3-C55; A5-B3-C31; A3-B3-C45; A4-B3-C21; A4-B3-C55; A5-B3-C32; A3-B3-C46; A4-B3-C22; A4-B3-C57; A5-B3-C33; A3-B3-C47; A4-B3-C23; A4-B3-C58; A5-B3-C34; A3-B3-C48; A4-B3-C24; A4-B3-C59; A5-B3-C35; A3-B3-C49; A4-B3-C25; A5-B3-C1; A5-B3-C36; A3-B3-C50; A4-B3-C26; A5-B3-C2; A5-B3-C37; A3-B3-C51; A4-B3-C27; A5-B 3 -C 3; A5-B3-C38; A3-B3-C52; A4-B3-C28; A5-B3-C4; A5-B3-C39; A3-B3-C53; A4-B3-C29; A5-B 3 -C 5; A5-B3-C40; A3-B3-C54; A4-B3-C30; A5-B 3 -C 6; A5-B3-C41; A3-B3-C55; A4-B3-C31; A5-B 3 -C 7; A5-B3-C42; A3-B3-C55; A4-B3-C32; A5-B3-C8; A5-B3-C43; A3-B3-C57; A4-B3-C33; A5-B3-C9; - A5-B3-C44;

-118A5-B3-C45;

A5-B3-C46;

A5-B3-C47;

A5-B3-C48;

A5-B3-C49;

A5-B3-C50;

A5-B3-C51;

A5-B3-C52;

A5-B3-C53;

A5-B3-C54;

A5-B3-C55;

A5-B3-C56;

A5-B3-C57;

A5-B3-C58;

A5-B3-C59;

A6-B3-C1;

A6-B3-C2;

A6-B3-C3;

A6-B3-C4;

A6-B3-C5;

A6-B3-C6;

A6-B3-C7;

A6-B3-C8 ;;

A6-B3-C9;

A6-B3-C10;

A6-B3-C11;

A6-B3-C12;

A6-B3-C13;

A6-B3-C14;

A6-B3-C15;

A6-B3-C16;

A6-B3-C17;

A6-B3-C18;

A6-B3-C19;

A6-B3-C20;

A6-B3-C21;

A6-B3-C22;

A6-B3-C23;

A6-B3-C24;

A6-B3-C25;

A6-B3-C26;

A6-B3-C27;

A6-B3-C28;

A6-B3-C29;

A6-B3-C30;

A6-B3-C31;

A6-B3-C32;

A6-B3-C33;

A6-B3-C34;

A6-B3-C35;

A6-B3-C36;

A6-B3-C37;

A6-B3-C38;

A6-B3-C39;

A6-B3-C40;

A6-B3-C41;

A6-B3-C42;

A6-B3-C43;

A6-B3-C44;

A6-B3-C45;

A6-B3-C46;

A6-B3-C47;

A6-B3-C48;

A6-B3-C49;

A6-B3-C50;

A6-B3-C51;

A6-B3-C52;

A6-B3-C53;

A6-B3-C54;

A6-B3-C55;

A6-B3-C55;

A6-B3-C57;

A6-B3-C58;

A6-B3-C59;

A7-B3-C1;

A7-B3-C2;

A7-B3-C3;

A7-B3-C4;

A7-B3-C5;

A7-B3-C6;

A7-B3-C7;

A7-B3-C8;

A7-B3-C9;

A7-B3-C10;

A7-B3-C11;

A7-B3-C12;

A7-B3-C13;

A7-B3-C14;

A7-B3-C15;

A7-B3-C16;

A7-B3-C17;

A7-B3-C18;

A7-B3-C19;

A7-B3-C20;

A7-B3-C21;

A7-B3-C22;

A7-B3-C23;

A7-B3-C24;

A7-B3-C25;

A7-B3-C26;

A7-B3-C27;

A7-B3-C28;

A7-B3-C29;

A7-B3-C30;

A7-B3-C31;

A7-B3-C32;

A7-B3-C33;

A7-B3-C34;

A7-B3-C35;

A7-B3-C36;

A7-B3-C37;

A7-B3-C38;

A7-B3-C39;

77-B3-C40;

77-B3-C41;

A7-B3-C42;

A7-B3-C43;

A7-B3-C44;

A7-B3-C45;

A7-B3-C46;

A7-B3-C47;

77-B3-C48;

A7-B3-C49;

A7-B3-C50;

A7-B3-C51;

77-B3-C52;

A7-B3-C53;

A7-B3-C54;

A7-B3-C55;

A7-B3-C56;

A7-B3-C57;

A7-B3-C58;

A7-B3-C59;

A8-B3-C1;

A8-B3-C2;

A8-B3-C3;

A8-B3-C4;

A8-B3-C5;

A8-B3-C6;

A8-B3-C7;

A8-B3-C8;

A8-B3-C9;

A8-B3-C10;

A8-B3-C11;

A8-B3-C12;

A8-B3-C13;

A8-B3-C14;

A8-B3-C15;

A8-B3-C16;

A8-B3-C17;

A8-B3-C18;

A8-B3-C19;

A8-B3-C20;

A8-B3-C21;

A8-B3-C22;

A8-B3-C23;

A8-B3-C24;

A8-B3-C25;

A8-B3-C26;

A8-B3-C27;

A8-B3-C28;

A8-B3-C29;

A8-B3-C30;

A8-B3-C31;

A8-B3-C32;

A8-B3-C33;

A8-B3-C34;

A8-B3-C35;

A8-B3-C36;

A8-B3-C37;

A8-B3-C38;

A8-B3-C39;

A8-B3-C40;

A8-B3-C41;

A8-B3-C42;

-119

44 · ·

A8-B3-C43; A9-B3-CX9; 99-B3-C54; AX0-B3-C30; A1X-B3-C6; A8-B3-C44; A9-B3-C20; 99-B3-C55; A10-B3-C31; A11-B3-C7; A8-B3-C45; 99-B3-C21; 99-B3-C56; AX0-B3-C33; A1X-B3-C8; A8-B3-C46; A9-B3-C22; 99-B3-C57; AX0-B3-C33; AX1-B3-C8; - A8-B3-C47; 99-B3-C23; 99-B3-C58; A10-B3-C34; Al1-B3-C10; 88-B3-C48; 99-B3-C24; A9-B3-CS9; AX0-B3-C35; AXX-B3-CXX 88-B3-C49; 99-B3-C25; A10-B3-CX; AX0-B3-C36; AX1-B3-C12; A8-B3-CS0; A9-B3-C26; AX0-B3-C2; AX0-B3-C36; A11-B3-C13; A8-B3-C5X; 99-B3-C27; AX0-B3-C3; A10-B3-C38; AII-B 3 -CX 4; 88-B3-C52; A9-B3-C28; AX0-B3-C4; A10-B3-C39; Al1-B3-C15; A8-B3-CS3; A9-B3-C29; AX0-B3-C4; AX0-B3-C40; A11-B3-CX6; A8-B3-C54; 99-B3-C30; A10-B3-CO; A10-B3-C41; AX1-B3-C17; A8-B3-C55; A9-B3-C3X; AX0-B3-C8; AX0-B3-C41; A11-B3-C18; A8-B3-C56; 99-B3-C32; AX0-B3-C7; A10-B3-C43; A11-B3-CX9; A8-B3-C57; 99-B3-C33; A10-B3-C9; A10-B3-C44; Al1-B3-C20; A8-B3-CS8; 99-B3-C34; A10-B3-C10; A10-B3-C45; A11-B3-C2X; A8-B3-C59; 99-B3-C35; A10-B3-C11; A10-B3-C46; A11-B3-C22; A9-B3-C1; 99-B3-C36; AX0-B3-C11; AX0-B3-C46; A1X-B3-C23; A9-B3-C2; 99-B3-C37; A10-B3-CX3; AX0-B3-C48; AX1-B3-C24; A9-B3-C3; 99-B3-C38; AX0-B3-CX3; AX0-B3-C50; A11-B3-C25; 9 9 -B 3 -C 4; 99-B3-C39; AX0-B3-C14; AX0-B3-C50; AX1-B3-C26; A9-B3-C5; 99-B3-C40; A10-B3-CX6; AX0-B3-C5X; A11-B3-C27; A9-B3-C6; 99-B3-C41; AX0-B3-CX8; A10-B3-C52; AX1-B3-C28; A9-B3-C7; 99-B3-C42; A10-B3-CX8; A10-B3-C53; A11-B3-C29; 99-B3-C8; 99-B3-C43; AX0-B3-CX8; A10-B3-C54; A1X-B3-C30; A9-B3-C9; 99-B3-C44; AX0-B3-C20; AX0-B3-C55; AX1-B3-C30; 99-B3-C10; 99-B3-C45; A10-B3-C21; A10-B3-C56; A11-B3-C32; A9-B3-C11; 99-B3-C46; A10-B3-C22; AX0-B3-C57; AXX-B3-C33 99-B3-CX2; 99-B3-C47; A10-B3-C23; . A10-B3-C58; AXX-B3-C33; 99-B3-CX3; 99-B3-C48; A10-B3-C24; AX0-B3-C59; AXX-B3-C40; 99-B3-CX4; 99-B3-C49; AX0-B3-C25; AXX-B3-CX; AXX-B3-C35; 99-B3-C15; 99-B3-C50; A10-B3-C26; AX1-B3-C2; A1X-B3-C37; 99-B3-C16; A9-B3-C5X; A10-B3-C27; AXX-B3-C3; AXX-B3-C38; A9-B3-C17; 99-B3-C52; A10-B3-C28; Al1-B3-C4; AX1-B3-C39; 99-B3-CX8; 99-B3-C53; A10-B3-C29; AX1-B3-C4; A11-B3-C40;

- 120-

AU-B3-C41; A12-B3-C17; A12-B3-C52; A13-B3-C28; A14-B3-C4; AU-B3-C42; A12-B3-C18; A12-B3-C53; A13-B3-C29; A14-B3-C5; AU-B3-C43; A12-B3-C19; A12-B3-C54; A13-B3-C30; A14-B3-C6; A11-B3-C44; A12-B3-C20; A12-B3-C55; A13-B3-C31; A14-B3-C7; A11-B3-C45; A12-B3-C21; A12-B3-C56; A13-B3-C32; A14-B3-C8; A11-B3-C46; A12-B3-C22; A12-B3-C57; A13-B3-C33; A14-B3-C9; A11-B3-C47; A12-B3-C23; A12-B3-C58; A13-B3-C34; A14-B3-C10; A11-B3-C48; A12-B3-C24; A12-B3-C59; A13-B3-C35; A14-B3-C11; A11-B3-C49; A12-B3-C25; A13-B3-C1; A13-B3-C36; A14-B3-Cl2; A11-B3-C50; A12-B3-C26; A13-B3-C2; A13-B3-C37; A14-B3-C13; A11-B3-C51; A12-B3-C27; A13-B3-C3; A13-B3-C38; A14-B3-C14; A11-B3-C52; A12-B3-C28; A13-B3-C4; A13-B3-C39; A14-B3-C15; A11-B3-C53; A12-B3-C29; A13-B3-C5; A13-B3-C40; A14-B3-C16; A11-B3-C54; A12-B3-C30; A13-B3-C6; A13-B3-C41; A14-B3-C17; A11-B3-C5S; A12-B3-C31; A13-B3-C7; A13-B3-C42; A14-B3-C18; A11-B3-C56; A12-B3-C32; A13-B3-C8; A13-B3-C43; A14-B3-C19; A11-B3-C57; A12-B3-C33; A13-B3-C9; A13-B3-C44; A14-B3-C20; A11-B3-C58; A12-B3-C34; A13-B3-C10; A13-B3-C45; A14-B3-C21; A11-B3-C59; A12-B3-C35; Al3-B3-C11; A13-B3-C46; A14-B3-C22; A12-B3-C1; A12-B3-C36; A13-B3-C12; A13-B3-C47; A14-B3-C23; A12-B3-C2; A12-B3-C37; A13-B3-C13; A13-B3-C48; A14-B3-C24; A12-B3-C3; A12-B3-C38; A13-B3-C14; A13-B3-C49; A14-B3-C25; AX2-B3-C4; A12-B3-C39; A13-B3-C15; A13-B3-C50; A14-B3-C26; A12-B3-C5; A12-B3-C40; A13-B3-C16; A13-B3-CS1; A14-B3-C27; A12-B3-C6; A12-B3-C41; A13-B3-C17; A13-B3-C52; A14-B3-C28; A12-B3-C7; A12-B3-C42; A13-B3-C18; A13-B3-C53; A14-B3-C29; A12-B3-C8; A12-B3-C43; A13-B3-C19; A13-B3-C54; A14-B3-C30; A12-B3-C9; A12-B3-C44; A13-B3-C20; A13-B3-C55; A14-B3-C31; A12-B3-C10; A12-B3-C45; A13-B3-C21; A13-B3-C56; A14-B3-C32; A12-B3-C11; A12-B3-C46; A13-B3-C22; A13-B3-C57; A14-B3-C33; A12-B3-C12; A12-B3-C47; A13-B3-C23; A13-B3-C58; A14-B3-C34; A12-B3-C13; A12-B3-C48; A13-B3-C24; A13-B3-C59; A14-B3-C35; A12-B3-C14; A12-B3-C49; A13-B3-C25; A14-B3-C1; A14-B3-C36; Al2-B3-C15; A12-B3-C50; A13-B3-C26; A14-B3-C2; A14-B3-C37; A12-B3-C16; A12-B3-C51; A13-B3-C27; 1414-B3-C3; A14-B3-C38;

- 121 • 9 .. .9 .9

9 '94-9 ·· \ ΐ; ί * · 9 9999>9;. · '9 · i ¹ 9 ·' 9 β

9 <· 9 ·· ···

A14-B3-C39;

A14-B3-C40;

A14-B3-C41;

A14-B3-C42;

A14-B3-C43;

A14-B3-C44;

A14-B3-C45;

A14-B3-C46;

A14-B3-C47;

A14-B3-C48;

A14-B3-C49;

A14-B3-CS0;

44-B3-C51;

A14-B3-C52;

A14-B3-C53;

A14-B3-C54;

A14-B3-C55;

A14-B3-C56;

A14-B3-C57;

A14-B3-C58;

A14-B3-C59;

A15-B3-C1;

A15-B3-C2;

A15-B3-C3;

A15-B3-C4;

A1S-B3-C5;

A15-B3-C6;

A15-B3-C7;

A15-B3-C8;

A15-B3-C9;

A15-B3-C10;

A15-B3-C11;

A15-B3-C12;

A15-B3-C13;

A15-B3-C14;

A15-B3-C15;

A15-B3-O6;

A15-B3-C17;

A15-B3-C18;

A15-B3-C19;

A1S-B3-C20;

A1S-B3-C21;

A15-B3-C22;

A15-B3-C23;

A15-B3-C24;

A1S-B3-C25;

A15-B3-C26;

A15-B3-C27;

A15-B3-C28;

A15-B3-C29;

A15-B3-C30;

A15-B3-C31;

A15-B3-C32;

A15-B3-C33;

A15tB3-C34;

A1S-B3-C35;

A15-B3-C36;

A15-B3-C37;

A15-B3-C38;

A15-B3-C39;

A15-B3-C40;

A1S-B3-C41;

A15-B3-C42;

A1S-B3-C43;

A15-B3-C44;

A15-B3-C45;

A15-B3-C46;

A1S-B3-C47;

A1S-B3-C48;

A15-B3-C49;

A15-B3-C50;

A15-B3-C51;

A15-B3-C52;

A15-B3-C53;

A15-B3-C54;

A15-B3-C5S;

A1S-B3-C56;

A15-B3-C57;

A15-B3-C58;

A15-B3-C59;

A16-B3-C1;

A16-B3-C2;

A16-B3-C3;

A16-B3-C4; ,

A16-B3-C5;

A16-B3-C6;

A16-B3-C7;

A16-B3-C8;

A16-B3-C9;

A16-B3-C10;

A16-B3-C11;

A16-B3-C12;

A16-B3-C13;

A16-B3-C14;

A16-B3-C15;

A16-B3-C16;

A16-B3-C17;

A16-B3-C18;

A16-B3-C19;

A16-B3-C20;

A16-B3-C21;

A16-B3-C22;

A16-B3-C23;

A16-B3-C24;

A16-B3-C2S;

A16-B3-C26;

A16-B3-C27;

A16-B3-C28;

A16-B3-C29;

A16-B3-C30;

A16-B3-C31;

A16-B3-C32;

A16-B3-C33;

A16-B3-C34;

A16-B3-C35;

A16-B3-C36;

A16-B3-C37;

A16.B3-C38;

A16-B3-C39;

A16-B3-C40;

A16-B3-C41;

A16-B3-C42;

A16-B3-C43;

A16-B3-C44;

A16-B3-C45;

A16-B3-C46;

A16-B3-C47;

A16-B3-C48;

A16-B3-C49;

A16-B3-C50;

A16-B3-C51;

A16-B3-C52;

A16-B3-C53;

A16-B3-C54;

A16-B3-C55;

A16-B3-C56;

A16-B3-C57;

A16-B3-C58;

A16-B3-CS9;

A17-B3-C1;

A17-B3-C2;

A17-B3-C3;

A17-B3-C4;

A17-B3-C5;

A17-B3-C6;

A17-B3-C7;

A17-B3-C8;

A17-B3-C9;

A17-B3-C10;

A17-B3-C11;

A17-B3-C12;

A17-B3-C13;

A17-B3-C14;

A17-B3-C15;

A17-B3-C16;

A17-B3-C17;

A17-B3-C18;

A17-B3-C19;

A17-B3-C20;

A17-B3-C21;

A17-B3-C22;

A17-B3-C23;

A17-B3-C24;

A17-B3-C25;

A17-B3-C26;

A17-B3-C27;

A17-B3-C28;

A17-B3-C29;

A17-B3-C30;

A17-B3-C31;

A17-B3-C32;

A17-B3-C33;

A17-B3-C34;

A17-B3-C35;

A17-B3-C36;

• ·· ββ ⁴ β β β · * · ·

-122- • '•• β ··· · • · · . · · · · Β · • · • · · β · * ·. · ·. . ·.> · • · · · ^ - · _4 • · ··· β · · <-. · * ·. • · · β β ·· · ·· A17-B3-C37; A18-B3-C13; A18-B3-C48; A19-B3-C24; A19-B3-C59; A17-B3-C38; A18-B3-C14; A18-B3-C49; A19-B3-C25; A20-B3-C1; A17-B3-C39; A18-B3-C15; A18-B3-C50; A19-B3-C26; A20-B3-C2; A17-B3-C4O; A18-B3-C16; A18-B3-C51; A19-B3-C27; A20-B3-C3; A17-B3-C41; A18-B3-C17; A18-B3-C52; A19-B3-C28; A20-B3-C4; A17-B3-C42; A18-B3-C18; A18-B3-C53; A19-B3-C29; A20-B3-C5; A17-B3-C43; A18-B3-C19; A18-B3-C54; A19-B3-C30; A20-B3-C6; A17-B3-C44; A18-B3-C20; A18-B3-C55; A19-B3-C31; A20-B3-C7; A17-B3-C45; A18-B3-C21; A18-B3-C56; A19-B3-C32; A20-B3-C8; A17-B3-C46; A18-B3-C22; A18-B3-C57; A19-B3-C33; A20-B3-C9; A17-B3-C47; A18-B3-C23; A18-B3-C58; A19-B3-C34; A20-B3-C10; A17-B3-C48; A18-B3-C24; A18-B3-C59; A19-B3-C35; A20-B3-C11; A17-B3-C49; A18-B3-C25; A19-B3-C1; A19-B3-C36; A20-B3-C12; A17-B3-C50; A18-B3-C26; A19-B3-C2; A19-B3-G37; A20-B3-C13; A17-B3-C51; A18-B3-C27; A19-B3-C3; A19-B3-C38; A20-B3-C14; A17-B3-C52; A18-B3-C28; A19-B3-C4; A19-B3-C39; A20-B3-C15; A17-B3-C53; A18-B3-C29; A19-B3-C5; A19-B3-C40; A20-B3-C16; A17-B3-C54; A18-B3-C30; A19-B3-C6; A19-B3-C41; A20-B3-C17; A17-B3-C55; A18-B3-C31; A19-B3-C7; A19-B3-C42; A20-B3-C18; A17-B3-C56; A18-B3-C32; A19-B3-C8; A19-B3-C43; A20-B3-C19; A17-B3-C57; A18-B3-C33; A19-B3-C9; A19-B3-C44; A20-B3-C20; A17-B3-C58; A18-B3-C34; A19-B3-C10; A19-B3-C45; A20-B3-C21; A17-B3-C59; A18-B3-C35; A19-B3-C11; A19-B3-C46; A20-B3-C22; A18-B3-C1; A18-B3-C36; A19tB3-C12; A19-B3-C47; A20-B3-C23; A18-B3-C2; A18-B3-C37; A19-B3-C13; A19-B3-C48; A20-B3-C24; A18-B3-C3; A18-B3-C38; A19-B3-C14; A19-B3-C49; A20-B3-C25; A18-B3-C4; A18-B3-C39; A19-B3-C15; A19-B3-C50; A20-B3-C26; A18-B3-C5; A18-B3-C40; A19-B3-C16; A19-B3-C51; A20-B3-C27; A18-B3-C6; A18-B3-C4I; A19-B3-C17; A19-B3-C52; A20-B3-C28; A18-B3-C7; A18-B3-C42; A19-B3-C18; A19-B3-C53; A20-B3-C29; A18-B3-C8; A18-B3-C43; A19-B3-C19; A19-B3-C54; A20-B3-C30; A18-B3-C9; A18-B3-C44; A19-B3-C20; A19-B3-C55; A20-B3-C31; A18-B3-C10; A18-B3-C45; A19-B3-C21; A19-B3-C56; A20-B3-C32; A18-B3-C11; A18-B3-C46; A19-B3-C22; A19-B3-C57; A20-B3-C33; A18-B3-C12; A18-B3-C47; A19-B3-C23; A19-B3-C58; A20-B3-C34; *

• _T · *: r .. «

- 123

XŤSŘESÍ

• · »». ......;

··· · · · ····· · ··

A20-B3-C35; A21-B3-C11; A21-B3-C46; A22-B3-C22; A22-B3-C57; A20-B3-C36; A21-B3-C12; A21-B3-C47; A22-B3-C23; A22-B3-C58; A20-B3-C37; A21-B3-C13; A21-B3-C48; A22-B3-C24; A22-B3-C59; A20-B3-C38; A21-B3-C14; A21-B3-C49; A22-B3-C25; A23-B3-C1; A20-B3-C39; A21-B3-C15; A21-B3-C50; A22-B3-C26; A23-B3-C2; A20-B3-C40; A21-B3-C16; A21-B3-C51; A22-B3-C27; A23-B3-C3; A20-B3-C41; A21-B3-C17; A21-B3-C52; A22-B3-C28; A23-B3-C4; A20-B3-C42; A21-B3-C18; A21-B3-C53; A22-B3-C29; A23-B3-C5; - A20-B3-C43; A21-B3-C19; A21-B3-C54; A22-B3-C30; A23-B3-C6; A20-B3-C44; A21-B3-C20; A21-B3-C55; A22-B3-C31; A23-B3-C7; A20-B3-C45; A21-B3-C21; A21-B3-C56; A22-B3-C32; A23-B3-C8; A20-B3-C46; A21-B3-C22; A21-B3-C57; A22-B3-C33; A23-B3-C9; A20-B3-C47; A21-B3-C23; A21-B3-C58; A22-B3-C34; A23-B3-C10; A20-B3-C48; A21-B3-C24; A21-B3-C59; A22-B3-C35; A23-B3-C11; A20-B3-C49; A21-B3-C25; A22-B3-C1; A22-B3-C36; A23-B3-C12; A20-B3-C50; A21-B3-C26; A22-B3-C2; A22-B3-C37; A23-B3-C13; A20-B3-C51; A21-B3-C27; A22-B3-C3; A22-B3-C38; A23-B3-C14; A20-B3-C52; A21-B3-C28; A22-B3-C4; A22-B3-C39; A23-B3-C15; A20-B3-C53; A21-B3-C29; A22-B3-C5; A22-B3-C40; A23-B3-C16; A20-B3-C54; A21-B3-C30; A22-B3-C6; A22-B3-C41; A23-B3-C17; - A20-B3-C55; A21-B3-C31; A22-B3-C7; A22-B3-C42; A23-B3-C18; A20-B3-C56; A21-B3-C32; A22-B3-C8; A22-B3-C43; A23-B3-C19; A20-B3-C57; A21-B3-C33; A22-B3-C9; A22-B3-C44; A23-B3-C20; A20-B3-C58; A21-B3-C34; A22-B3-C10; A22-B3-C45; A23-B3-C21; - A20-B3-C59; A21-B3-C35; A22-B3-C11; ^Λ A22-B3-C46; A23-B3-C22; A21-B3-C1; A21-B3-C36; A22-B3-C12; A22-B3-C47; A23-B3-C23; A21-B3-C2; A21-B3-C37; A22-B3-C13; A22-B3-C48; A23-B3-C24; A21-B3-C3; A21-B3-C38; A22-B3-C14; A22-B3-C49; ' A23-B3-C25; A21-B3-C4; A21-B3-C39; A22-B3-C15; A22-B3-C50; A23-B3-C26; A21-B3-C5; A21-B3-C40; A22-B3-C16; A22-B3-C51; A23-B3-C27; A21-B3-C6; A21-B3-C41; A22-B3-C17; A22-B3-C52; A23-B3-C28; A21-B3-C7; A21-B3-C42; A22-B3-C18; A22-B3-C53; A23-B3-C29; A21-B3-C8; A21-B3-C43; A22-B3-C19; ’ A22-B3-C54; A23-B3-C30; A21-B3-C9; A21-B3-C44; A22-B3-C20; A22-B3-C55; A23-B3-C31; .-in A21-B3 _: C10; A21-B3-C45; A22-B3-C21; A22-B3-C56; A23-B3-C32;

... ? -124 - • Φ 0 · · · • φ. ♦ • φ · φ • φ • Φ φ φφ • ♦ ♦. · •. · ',', ' φ φ Φ Φ · φβ φΥφ- · • β β Φ φ · · · φ A23-B3-C33; A24-B3-C9; A24-B3-C44; A25-B3-C20; A25-B3-C55; A23-B3-C34; A24-B3-C10; A24-B3-C45; A25-B3-C21; A25-B3-C56; A23-B3-C35; A24-B3-C1I; A24-B3-C46; A25-B3-C22; A25-B3-C57; A23-B3-C36; A24-B3-C12; A24-B3-C47; A25-B3-C23; A25-B3-C58; A23-B3-C37; A24-B3-C13; A24-B3-C48; A25-B3-C24; A25-B3-C59; A23-B3-C38; A24-B3-C14; A24-B3-C49; A25-B3-C25; A26-B3-C1; A23-B3-C39; A24-B3-C15; A24-B3-C50; A25-B3-C26; A26-B3-C2; A23-B3-C40; A24-B3-C16; A24-B3-C51; A25-B3-C27; A26-B3-C3; A23-B3-C41; A24-B3-C17; A24-B3-C52; A25-B3-C28; A26-B3-C4; A23-B3-C42; A24-B3-C18; A24-B3-C53; A25-B3-C29; A26-B3-C5; A23-B3-C43; A24-B3-C19; A24-B3-G54; A25-B3-C30; A26-B3-C6; A23-B3-C44; A24-B3-C20; A24-B3-CS5; A25-B3-C31; A26-B3-C7; A23-B3-C45; A24-B3-C21; A24-B3-C56; A25-B3-C32; A26-B3-C8; A23-B3-C46; A24-B3-C22; A24-B3-C57; A25-B3-C33; A26-B3-C9; A23-B3-C47; A24-B3-C23; A24-B3-C58; A25-B3-C34; A26-B3-C10; A23-B3-C48; A24-B3-C24; A24-B3-C59; A25-B3-C35; A26-B3-C11; A23-B3-C49; A24-B3-C25; A25-B3-C1; A25-B3-C36; A26-B3-C12; A23-B3-C50; A24-B3-C26; A25-B3-C2; A25-B3-C37; A26-B3-C13; A23-B3-C51; A24-B3-C27; A25-B3-C3; A25-B3-C38; A26-B3-C14; A23-B3-C52; - A24-B3-C28; A25-B3-C4 A25-B3-C39; A26-B3-C15; A23-B3-C53; A24-B3-C29; A25-B3-C5; A25-B3-C40; A26.B3-C16; A23-B3-C54; A24-B3-C30; A25-B3-C6; A25-B3-C41; A26-B3-C17; A23-B3-C55; A24-B3-C31; A25-B3-C7; A25-B3-C42; A26-B3-C18; A23-B3-C56; A24-B3-C32; A25-B3-C8; A25-B3-C43; A26-B3-C19; A23-B3-C57; A24-B3-C33; A25-B3-C9; A25-B3-C44; A26-B3-C20; A23-B3-C58; A24-B3-C34; . A25-B3-C10; A25-B3-C45; A26-B3-C21; A23-B3-C59; A24-B3-C35; A25-B3-C11; A25-B3-C46; A26-B3-C22; A24-B3-C1; A24-B3-C36; A25-B3-C12; A25-B3-C47; A26-B3-C23; A24-B3-C2; A24-B3-C37; A25-B3-C13; A25-B3-C48; A26-B3-C24; A24-B3-C3; A24-B3-C38; A2S-B3-C14; A25-B3-C49; A26-B3-C25; A24-B3-C4; A24-B3-C39; A25-B3-C15; A25-B3-C50; A26-B3-C26; A24-B3-C5; A24-B3-C40; A25-B3-C16; A25-B3-C51; A26-B3-C27; A24-B3-C6; A24-B3-C41; A25-B3-CX7; A25-B3-C52; A26-B3-C28; A24-B3-C7; A24-B3-C42; A25-B3-C18; A25-B3-C53; A26-B3-C29; A24-B3-C8; A24-B3-C43; A2S-B3-C19; A25-B3-C54; A26-B3-C30;

• 9

125 A26-B3-C31;

A26-B3-C32;

A26-B3-C33;

A26-B3-C34;

A26-B3-C35;

A26-B3-C36;

A26-B3-C37;

A26-B3-C38;

A26-B3-C39;

A26-B3-C40;

A26-B3-C41;

A26-B3-C42;

A26-B3-C43;

A26-B3-C44;

A26-B3-C45;

A26-B3-C46;

A26-B3-C47;

A26-B3-C48;

A26-B3-C49;

A26-B3-C50;

A26-B3-C51;

A26-B3-C52;

A26-B3-CS3;

A26-B3-C54;

A26-B3-C55;

A26-B3-C56;

A26-B3-C57;

A26-B3-C58;

A26-B3-C59;

A27-B3-C1;

A27-B3-C2;

A27-B3-C3;

A27-B3-C4;

A27-B3-C5;

A27-B3-C6;

A27-B3-C7;

A27-B3-C8;

A27-B3-C9;

A27-B3-C10;

A27-B3-C11;

A27-B3-C12;

A27-B3-C13;

A27-B3-C14;

A27-B3-C15;

A27-B3-C16;

A27-B3-C17;

A27-B3-C18;

A27-B3-C19;

A27-B3-C20;

A27-B3-C21;

A27-B3-C22;

A27-B3-C23;

A27-B3-C24;

A27-B3-C25;

A27-B3-C26;

A27-B3-C27;

A27-B3-C28;

A27-B3-C29;

A27-B3-C30;

A27-B3-C31;

A27-B3-C32;

A27-B3-C33;

A27-B3-C34;

A27-B3-C35;

A27-B3-C36;

A27-B3-C37;

A27-B3-C38;

A27-B3-C39;

A27-B3-C40;

A27-B3-C41;

A27-B3-C42;

A27-B3-C43;

A27-B3-C44;

A27-B3-C45;

A27-B3-C46;

A27-B3-C47;

A27-B3-C48;

A27-B3-C49;

A27-B3-CS0;

A27-B3-CS2;

A27-B3-C52;

A27-B3-C53;

A27-B3-CS4;

A27-B3-C5S;

A27-B3-C56;

A27-B3-C57;

A27-B3-C58;

A27-B3-C59;

A28-B3-C1;

A28-B3-C2;

A28-B3-C3;

A28-B3-C4;

A28-B3-C5;

A28-B3-C6;

A28-B3-C7;

A28-B3-C8;

A28-B3-C9;

A28-B3-C10;

A2S-B3-C11;

A28-B3-C12;

A28-B3-C13;

A28-B3-C14;

A28-B3-C15;

A28-B3-C16;

A28-B3-C17;

A28-B3-C18;

A28-B3-C19;

A28-B3-C20;

A28-B3-C21;

A28-B3-C22;

A28-B3-C23;

A28-B3-C24;

A28-B3-C25;

A28-B3-C26;

A28-B3-C27;

A28-B3-C28;

A28-B3-C29;

A28-B3-C30;

A28-B3-C31;

A28-B3-C32;

A28-B3-C33;

A28-B3-C34;

A28-B3-C35;

A28-B3-C36;

A28-B3-C37;

A28-B3-C38;

A28-B3-C39;

A28-B3-C40;

A28-B3-C41;

A28-B3-C42;

A28-B3-C43;

A28-B3-C44;

A28-B3-C45;

A28-B3-C46;

A28-B3-C47;

A28-B3-C48;

A28-B3-C49;

A28-B3-C50;

A28-B3-C51;

A28-B3-C52;

A28-B3-CS3;

A28-B3-C54;

A28-B3-C55;

A28-B3-C56;

A28-B3-C57;

A28-B3-C58;

A28-B3-C59;

A29-B3-C1;

A29-B3-C2;

A29-B3-C3;

A29-B3-C4;

A29-B3-C5;

A29-B3-C6;

A29-B3-C7;

A29-B3-C8;

A29-B3-C9;

A29-B3-C10;

A29-B3-C11;

A29-B3-C12;

A29-B3-C13;

A29-B3-C14;

A29-B3-C15;

A29-B3-C16;

A29-B3-C17;

A29-B3-C18;

A29-B3-C19;

A29-B3-C20;

A29-B3-C21;

A29-B3-C22;

A29-B3-C23;

A29-B3-C24;

A29-B3-C25;

A29-B3-C26;

A29-B3-C27;

A29-B3-C28;

- 126 • 09 »9 · ··»

9 9 '· 9 9 9 9 9 99 ·· * I · ♦ ί, ·· * • 9 9 9 $ 9 9999999 9 ^ 9 ^.

9 9 9 9 9 9 '9'

999 99 99 99 99 999

A29-B3-C29; A30-B3-C5; A30-B3-C40; A31-B3-C16; A31-B3-C51; A29-B3-C30; A30-B3-C6; A30-B3-C41; A31-B3-C17; A31-B3-C52; A29-B3-C31; A30-B3-C7; A30-B3-C42; A31-B3-C18; A31-B3-C53; A29-B3-C32; A30-B3-C8; A30-B3-C43; A31-B3-C19; A31-B3-C54; A29-B3-C33; A30-B3-C9; A30-B3-C44; A31-B3-C20; A31-B3-C55; A29-B3-C34; A30-B3-C10; A30-B3-C45; A31-B3-C21; A31-B3-C56; A29-B3-C35; A30-B3-C11; A30-B3-C46; A31-B3-C22; A31-B3-C57; A29-B3-C36; A30-B3-C12; A30-B3-C47; A31-B3-C23; A31-B3-C58; A29-B3-C37; A30-B3-C13; A30-B3-C48; A31-B3-C24; A31-B3-C59; A29-B3-C38; A30-B3-C14; A30-B3-C49; A31-B3-C25; A32-B3-C1; A29-B3-C39; A30-B3-C15; A30-B3-C50; A31-B3-C26; A32-B3-C2; A29-B3-C40; A30-B3-C16; A30-B3-C51; A31-B3-C27; A32-B3-C3; A29-B3-C41; A30-B3-C17; A30-B3-C52; A31-B3-C28; A32-B3-C4; A29-B3-C42; A30-B3-C18; A30-B3-C53; A31-B3-C29; A32-B3-C5; A29-B3-C43; A30-B3-C19; A30-B3-C54; A31-B3-C30; A32-B3-C6; A29-B3-C44; A30-B3-C20; A30-B3-C55; A31-B3-C31; A32-B3-C7; A29-B3-C45; A30-B3-C21; A30-B3-C56; A31-B3-C32; A32-B3-C8; A29-B3-C46; A30-B3-C22; A30-B3-C57; A31-B3-C33; A32-B3-C9; A29-B3-C47; A30-B3-C23; A30-B3-C58; A31-B3-C34; A32-B3-C10; A29-B3-C48; A30-B3-C24; A30-B3-C59; A31-B3-C35; A32-B3-C11; A29-B3-C49; A30-B3-C25; A31-B3-C1; A31-B3-C36; A32-B3-C12; A29-B3-C50; A30-B3-C26; A31-B3-C2; A31-B3-C37; A32-B3-C13; A29-B3-C51; A30-B3-C27; A31-B3-C3; A31-B3-C38; A32-B3-C14; A29-B3-C52; A30-B3-C28; A31-B3-C4; A31-B3-C39; A32-B3-C15; A29-B3-C53; A30-B3-C29; A31-B3-C5; A31-B3-C40; A32-B3-C16; A29-B3-C54; A30-B3-C30; A31-B3-C6; A31-B3-C41; A32-B3-C17; A29-B3-C55; A30-B3-C31; A31-B3-C7; A31-B3-C42; A32-B3-C18; A29-B3-C56; A30-B3-C32; A31-B3-C8; A31-B3-C43; A32-B3-C19; A29-B3-C57; A30-B3-C33; A31-B3-C9; A31-B3-C44; A32-B3-C20; A29-B3-C58; A30-B3-C34; A31-B3-C10; A31-B3-C45; A32-B3-C21; A29-B3-C59; A30-B3-C35; A31-B3-C1I; A31-B3-C46; A32-B3-C22; A30-B3-C1; A30-B3-C36; A31-B3-C12; A31-B3-C47; A32-B3-C23; A30-B3-C2; A30-B3-C37; A31-B3-C13; A31-B3-C48; A32-B3-C24; A30-B3-C3; A30-B3-C38; A31-B3-C14; A31-B3-C49; A32-B3-C25; A30-B3-C4; A30-B3-C39; A31-B3-C15; A31-B3-C50; A32-B3-C26;

-127- “Γ« • 1 · • * ·· « • · • 4 · 4 • 44 4 4 4 ·· '», / Γ».' '· - 4 · ·· · 4 4 '4' 4 4 «3 4» A32-B3-C27; A33-B3-C3; A33-B3-C38; A34-B3-C14; A34-B3-C49; A32-B3-C28; A33-B3-C4; A33-B3-C39; A34-B3-C15; A34-B3-C50; A32-B3-C29; A33-B3-C5; A33-B3-C40; A34-B3-C16; A34-B3-C51; A32-B3-C30; A33-B3-C6; A33-B3-C41; A34-B3-C17; A34-B3-C53: A32-B3-C31; A33-B3-C7; A33-B3-C42; A34-B3-C1S; A34-B3-C53; A32-B3-C32; A33-B3-C8; A33-B3-C43; A34-B3-C19; A34-B3-C54; A32-B3-C33; A33-B3-C9; A33-B3-C44; A34-B3-C20; A34-B3-CSS; A32-B3-C34; A33-B3-C10; A33-B3-C45; A34-B3-C21; A34-B3-C56; A32-B3-C35; A33-B3-C11; A33-B3-C46; A34-B3-C22; A34-B3-C57; A32-B3-C36; A33-B3-C12; A33-B3-C47; A34-B3-C23; A34-B3-C58; A32-B3-C37; A33-B3-C13; A33-B3-C48; A34-B3-C24; A34-B3-C59; A32-B3-C38; A33-B3-C14; A33-B3-C49; A34-B3-C25; A35-B3-C1; A32-B3-C39; A33-B3-C15; A33-B3-C50; A34-B3-C26; A35-B3-C2; A32-B3-C40; A33-B3-C16; A33-B3-C51; A34-B3-C27; A35-B3-C3; A32-B3-C41; A33-B3-C17; A33-B3-C52; A34-B3-C28; A35-B3-C4; A32-B3-C42; A33-B3-C18; A33-B3-C53; A34-B3-C29; A35-B3-C5; A32-B3-C43; A33-B3-C19; A33-B3-C54; A34-B3-C30; A35-B3-C6; A32-B3-C44; A33-B3-C20; A33-B3-C55; A34-B3-C31; A35-B3-C7; A32-B3-C45; A33-B3-C21; A33-B3-C56; A34-B3-C32; A35-B3-C8; A32-B3-C46; A33-B3-C22; A33-B3-C57; A34-B3-C33; A35-B3-C9; A32-B3-C47; A33-B3-C23; A33-B3-C58; A34-B3-C34; A35-B3-C10; A32-B3-C48; A33-B3-C24; A33-B3-C59; A34-B3-C35; A35-B3-C11; A32-B3-C49; A33-B3-C25; A34-B3-C1; A34-B3-C36; A35-B3-C12; A32-B3-C50; A33-B3-C26; A34-B3-C2; A34-B3-C37; A35-B3-C13; A32-B3-CS2; A33-B3-C27; A34-B3-C3; A34-B3-C38; A35-B3-C14; A32-B3-C52; A33-B3-C28; A34-B3-C4; A34-B3-C39; A35-B3-C15; A32-B3-CS3; A33-B3-C29; A34-B3-C5; A34-B3-C40; A35-B3-C16; A32-B3-C54; A33-B3-C30; A34-B3-C6; A34-B3-C41; A35-B3-C17; A32-B3-C55; A33-B3-C31; A34-B3-C7; A34-B3-C42; A35-B3-C18; A32-B3-C56; A33-B3-C32; A34-B3-C8; A34-B3-C43; A35-B3-C19; A32-B3-C57; A33-B3-C33; A34-B3-C9; A34-B3-C44; A35-B3-C20; A32-B3-C58; A33-B3-C34; A34-B3-C10; A34-B3-C45; A35-B3-C21; A32-B3-C59; A33-B3-C35; A34-B3-C11; A34-B3-C46; A35-B3-C22; A33-B3-C1; A33-B3-C36; A34-B3-C12; A34-B3-C47; A35-B3-C23; A33-B3-C2; A33-B3-C37; A34-B3-C13; A34-B3-C48; A35-B3-C24;

· ~ · - ·., »» 0 · » 0 · ·. * β » • · 0 0 . 0 0 ' , · - ν ' , - . .0 0 0 0.0 ' Τ 0 -128- • ¹ · 0 · 0 · 00 * * • 0 00 • 0 0 0 '' 0 Φ '0 ί'0 /' 0 0 '

A35-B3-C25; A1-B4-C1; A1-B4-C36; A2-B4-C12; A2-B4-C47; A35-B3-C20; A1-B4-C2; A1-B4-C37; A2-B4-C13; A2-B4-C48; A35-B3-C27; A1-B4-C3; A1-B4-C38; A2-B4-C14; A2-B4-C49; A35-B3-C28; A1-B4-C4; A1-B4-C39; A2-B4-C15; A2-B4-C50; A35-B3-C29; A1-B4-C5; A1-B4-C40; A2-B4-C16; A2-B4-C51; A35-B3-C30; A1-B4-C6; A1-B4-C41; A2-B4-C17; A2-B4-C52; A35-B3-C31; A1-B4-C7; A1-B4-C42; A2-B4-C18; A2-B4-C53; A35-B3-C32; A1-B4-C8; A1-B4-C43; A2-B4-C19; A2-B4-C54; A35-B3-C33; A1-B4-C9; A1-B4-C44; A2-B4-C20; A2-B4-C55; A3S-B3-C34; A1-B4-C10; A1-B4-C45; A2-B4-C21; A2-B4-C56; A35-B3-C35; A1-B4-C11; A1-B4-C46; A2-B4-C22; A2-B4-C57; A35-B3-C36; A1-B4-C12; A1-B4-C47; A2-B4-C23; A2-B4-C58; A35-B3-C37; A1-B4-C13; A1-B4-C48; A2-B4-C24; A2-B4-C59; A35-B3-C38; A1-B4-C14; A1-B4-C49; A2-B4-C25; A3-B4-C1; A35-B3-C39; A1-B4-C15; A1-B4-C50; A2-B4-C26; A3-B4-C2; A35-B3-C40; A1-B4-C16; A1-B4-C51; A2-B4-C27; A3-B4-C3; A35-B3-C41; A1-B4-C17; A1-B4-C52; A2-B4-C28; A3-B4-C4; A35-B3-C42; A1-B4-C18; A1-B4-C53; A2-B4-C29; A3-B4-C5; A35-B3-C43; A1-B4-C19; A1-B4-C54; A2-B4-C30; A3-B4-C6; A35-B3-C44; A1-B4-C20; A1-B4-C55; A2-B4-C31; -3-B4-C7; A35-B3-C45; A1-B4-C21; A1-B4-C56; A2-B4-C32; A3-B4-C8; A35-B3-C46; A1-B4-C22; A1-B4-C57; A2-B4-C33; A3-B4-C9; A35-B3-C47; A1-B4-C23; A1-B4-C58; A2-B4-C34; A3-B4-C10; A35-B3-C48; A1-B4-C24; A1-B4-C59; A2-B4-C35; A3-B4-C11; A35-B3-C49; A1-B4-C25; A2-B4-C1; A2-B4-C36; A3-B4-C12; A35-B3-C50; A1-B4-C26; A2-B4-C2; A2-B4-C37; A3-B4-C13; A35-B3-CS2; A1-B4-C27; A2-B4-C3; A2-B4-C38; A3-B4-C14; A35-B3-C52; A1-B4-C28; A2-B4-C4; A2-B4-C39; A3-B4-C15; A35-B3-C53; A1-B4-C29; A2-B4-C5; A2-B4-C40; A3-B4-C16; A35-B3-C54; A1-B4-C30; A2-B4-C6; A2-B4-C41; A3-B4-C17; A3S-B3-CS4; A1-B4-C31; A2-B4-C7; A2-B4-C42; A3-B4-C18; A35-B3-C56; A1-B4-C32; A2-B4-C8; A2-B4-C43; A3-B4-C19; A35-B3-C57; A1-B4-C33; A2-B4-C9; A2-B4-C44; A3-B4-C20; A35-B3-C58; A1-B4-C34; A2-B4-C10; A2-B4-C45; A3-B4-C21; A35-B3-C59; A1-B4-C35; A2-B4-C11; A2-B4-C46; A3-B4-C22;

I · · · · · · · · · · · · · · · · · · ·.

-129A3-B4-C23;

A3-B4-C24;

A3-B4-C25;

A3-B4-C26;

A3-B4-C27;

A3-B4-C28;

A3-B4-C29;

A3-B4-C30;

A3-B4-C31;

A3-B4-C32;

A3-B4-C33;

A3-B4-C34;

A3-B4-C35;

A3-B4-C36;

A3-B4-C37;

A3-B4-C38;

A3-B4-C39;

A3-B4-C40;

A3-B4-C41;

A3-B4-C42;

A3-B4-C43;

A3-B4-C44;

A3-B4-C45;

A3-B4-C46;

A3-B4-C47;

A3-B4-C48;

A3-B4-C49;

A3-B4-C50;

A3-B4-C51;

A3-B4-C52;

A3-B4-C53;

A3-B4-C54;

A3-B4-C55;

A3-B4-C55;

A3-B4-C57;

A3-B4-C58;

A3-B4-C59;

A4-B4-C1;

A4-B4-C2;

A4-B4-C3;

A4-B4-C4;

A4-B4-C5;

A4-B4-C6;

A4-B4-C7;

A4-B4-C8;

A4-B4-C9;

A4-B4-C10;

A4-B4-C11;

A4-B4-C12;

A4-B4-C13;

A4-B4-C14;

A4-B4-C15;

A4-B4-C16;

A4-B4-C17;

A4-B4-C18;

A4-B4-C19;

A4-B4-C20;

A4-B4-C21;

A4-B4-C22;

A4-B4-C23;

A4-B4-C24;

A4-B4-C25;

A4-B4-C26;

A4-B4-C27;

A4-B4-C28;

A4-B4-C29;

A4-B4-C30;

A4-B4-C31;

A4-B4-C32;

A4-B4-C33;

A4-B4-C34;

A4-B4-C35;

A4-B4-C36;

A4-B4-C37;

A4-B4-C38;

A4-B4-C39;

A4-B4-C40;

A4-B4-C41;

A4-B4-C42;

A4-B4-C43;

A4-B4-C44;

A4-B4-C45;

A4-B4-C46;

A4-B4-C47;

A4-B4-C48;

A4-B4-C49;

A4-B4-C50;

A4-B4-C51;

A4-B4-C52;

A4-B4-C53;

A4-B4-C54;

A4-B4-C55;

A4-B4-C55;

A4-B4-C57;

A4-B4-C58;

A4-B4-C59;

A5-B4-C1;

A5-B4-C2;

A5-B4-C3;

A5-B4-C4;

A5-B4-C5;

A5-B 4 -C 6;

A5-B4-C7;

A5-B4-C8;

A5-B4-C9;

A5-B4-C10;

A5-B4-C11;

A5-B4-Cl2;

AS-B4-C13;

A5-B4-C14;

A5-B4-C15;

A5-B4-C16;

A5-B4-C17;

A5-B4-C18;

A5-B4-C19;

A5-B4-C20;

A5-B4-C21;

A5-B4-C22;

A5-B4-C23;

A5-B4-C24;

A5-B4-C25;

A5-B4-C26;

A5-B4-C27;

A5-B4-C28;

A5-B4-C29;

55-B4-C30;

A5-B4-C31;

A5-B4-C32;

A5-B4-C33;

A5-B4-C34;

A5-B4-C35;

A5-B4-C36;

A5-B4-C37;

A5-B4-C38;

A5-B4-C39;

A5-B4-C40;

A5-B4-C41;

A5-B4-C42;

A5-B4-C43;

A5-B4-C44;

A5-B4-C45;

A5-B4-C46;

A5-B4-C47;

A5-B4-C48;

A5-B4-C49;

A5-B4-C50;

A5-B4-C51;

A5-B4-C52;

A5-B4-C53;

A5-B4-C54:

A5-B4-C55;

A5-B4-C56;

A5-B4-C57;

A5-B4-C58;

A5-B4-C59;

A6-B4-C1;

A6-B4-C2;

A6-B4-C3;

A6-B4-C4;

A6-B4-C5;

A6-B4-C6;

A6-B4-C7;

A6-B4-C8 ;;

A6-B4-C9;

A6-B4-C10;

A6-B4-C11;

A6-B4-C12;

A6-B4-C13;

A6-B4-C14;

A6-B4-C15;

A6-B4-C16;

A6-B4-C17;

A6-B4-C18;

A6-B4-C19;

A6-B4-C20;

with

-130- • 0 · 0 0 0 ' . 0 · · 0 0 0 0 0 0 0 0 0 0 0. 0 0 «« · 0 '0 0''0 · 0' 0 0 0 · '0 · 0 0 0 0 0 0''0+ ^Γ - · 0 0 0 0 9 0 0 -¼ · 9 A6-B4-C21; A6-B4-C55; 77-B4-C32; . A8-B4-C8; A8-B4-C43; A6-B4-C22; A6-B4-C57; A7-B4-C33; A8-B4-C9; A8-B4-C44; A6-B4-C23; A6-B4-C58; A7-B4-C34; A8-B4-C10; A8-B4-C45; A6-B4-C24; A6-B4-C59; 77-B4-C35; A8-B4-C11; A8-B4-C46; A6-B4-C25; A7-B4-C1; 77-B4-C36; A8-B4-C12; A8-B4-C47; A6-B4-C26; A7-B4-C2; A7-B4-C37; A8-B4-C13; A8-B4-C48; A6-B4-C27; A7-B4-C3; A7-B4-C38; A8-B4-C14; 88-B4-C49; A6-B4-C28; A7-B4-C4; A7-B4-C39; A8-B4-C15; A8-B4-C50; A6-B4-C29; A7-B4-C5; 77-B4-C40; A8-B4-CX6; A8-B4-C5X; A6-B4-C30; A7-B4-C6; A7-B4-C4I; 88-B4-CX7; A8-B4-C52; A6-B4-C3X; A7-B4-C7; A7-B4-C42; A8-B4-C18; A8-B4-C53; A6-B4-C32; A7-B4-C8; A7-B4-C43; A8-B4-C19; A8-B4-C54; A6-B4-C33; A7-B4-C9; A7-B4-C44; A8-B4-C20; A8-B4-C55; A6-B4-C34; 77-B4-C10; A7-B4-C45; A8-B4-C2X; A8-B4-C56; A6-B4-C35; A7-B4-C11; 77-B4-C46; A8-B4-C22; A8-B4-C57; A6-B4-C36; 77-B4-CX2; A7-B4-C47; A8-B4-C23; 88-B4-C58; A6-B4-C37; A7-B4-C13; 77-B4-C48; A8-B4-C24; A8-B4-C59; A6-B4-C38; A7-B4-C14; 77-B4-C49; A8-B4-C25; A9-B4-C1; A6-B4-C39; A7-B4-C15; A7-B4-C50; A8-B4-C26; A9-B4-C2; A6-B4-C40; A7-B4-C16; A7-B4-C5X; A8-B4-C27; A9-B4-C3; A6-B4-C4X; A7-B4-CX7; 77-B4-C52; A8-B4-C28; 99-B4-C4; A6-B4-C42; * A7-B4-C18; 77-B4-C53; A8-B4-C29; A9-B4-C5; A6-B4-C43; A7-B4-C19; A7-B4-C54; A8-B4-C30; A9-B4-C6; A6-B4-C44; A7-B4-C20; A7-B4-C55; A8-B4-C31; A9-B4-C7; A6-B4-C45; A7-B4-C21; A7-B4-C56; A8-B4-C32; A9-B4-C8; A6-B4-C46; A7-B4-C22; 77-B4-C57; A8-B4-C33; A9-B4-C9; A6-B4-C47; A7-B4-C23; 77-B4-C58; A8-B4-C34; 99-B4-C10; A6-B4-C48; A7-B4-C24; A7-B4-C59; 88-B4-C35; 99-B4-CXI; A6-B4-C49; A7-B4-C25; A8-B4-C1; A8-B4-C36; 99-B4-C12; A6-B4-C50; A7-B4-C26; 8 8 -B 4 -C 2; A8-B4-C37; A9-B4-C13; A6-B4-C51; A7-B4-C27; A8-B4-C3; A8-B4-C38; A9-B4-C14; A6-B4-C52; A7-B4-C28; A8-B4-C4; A8-B4-C39; A9-B4-C15; A6-B4-C53; A7-B4-C29; A8-B4-C5; A8-B4-C40; 99-B4-CX6; A6-B4-C54; A7-B4-C30; A8-B4-C6; A8-B4-C41; 99-B4-CX7; A6-B4-C55; A7-B4-C3X; A8-B4-C7; A8-B4-C42; 99-B4-CX8;

- 131-

φ φ

A9-B4-C19;

A9-B4-C20;

A9-B4-C21;

A9-B4-C22;

A9-B4-C23;

A9-B4-C24;

99-B4-C2S;

A9-B4-C26;

A9-B4-C27;

A9-B4-C28;

99-B4-C29;

99-B4-C30;

99-B4-C31;

99-B4-C32;

99-B4-C33;

99-B4-C34;

A9-B4-C35;

99-B4-C36;

99-B4-C37;

-? 9 - B 4 - C 38; -? 9 - B 4 - C 39; 99-B4-C40; 99-B4-C41; 99-B4-C42; A9-B4-C43; 99-B4-C44; 99-B4-C45; 99-B4-C46; 99-B4-C47; 99-B4-C48; 99-B4-C49; 99-B4-C50; 99-B4-C51; 99 -B4-C52; 99-B4-C53;

99-B4-C54;

A.9-B4-C55;

99-B4-C56;

99-B4-C57;

99-B4-C58;

99-B4-C59;

A10-B4-C1;

A10-B4-C2;

A10-B4-C3;

A10-B4-C4;

A10-B4-C5;

A10-B4-C6;

A10-B4-C7;

A10-B4-C8;

A10-B4-C9;

A10-B4-C10;

A10-B4-C11;

A10-B4-C12;

A10-B4-C13;

A10-B4-C14; A10-B4-C49;

A10-B4-C15; A10-B4-CS0;

A10-B4-C16;

A10-B4-C17;

A10-B4-C18;

AW - B4 - C19;

A10-B4-C20;

A10-B4-C21;

A10-B4-C22;

A10-B4-C23;

A10-B4-C24;

A10-B4-C25;

A10-B4-C26;

A10-B4-C27;

A1Q-B4-C28;

A10-B4-C29;

A10-B4-C30;

A10-B4-C31;

A10-B4-C32;

A10-B4-C33;

A10-B4-C34;

A10-B4-C35;

A10-B4-C36;

A10-B4-C37;

A10-B4-C38;

A10-B4-C39;

A10-B4-C40;

A10-B4-C41;

A10-B4-C42;

A10-B4-C43;

A10-B4-C44;

A10-B4-C4S;

A10-B4-C47:

A10-B4-C47;

A10-B4-C48;

A10-B4-C51;

A10-B4-CS2;

A10-B4-C53;

A10-B4-C54;

A10-B4-C55;

A10-B4-C56;

A10-B4-C57;

A10-B4-C58;

A10-B4-C59;

A11-B4-C1;

A11-B4-C2;

Al-B4-C3; ’

A11-B4-C4;

A11-B4-C5;

A11-B4-C6;

A11-B4-C7;

A11-B4-C8;

AU-B4-C9;

A11-B4-C10;

A11-B4-C11;

A11-B4-C12;

A11-B4-C13;

A11-B4-C14;

A11-B4-C15;

A11-B4-C16;

A11-B4-C17;

A11-B4-C18;

AU-B4-C19;

A11-B4-C20;

A11-B4-C21;

A11-B4-C22;

A11-B4-C23;

A1I-B4-C24;

A11-B4-C25;

A11-B4-C26;

A11-B4-C27;

A11-B4-C28;

A11-B4-C29;

A11-B4-C30;

A11-B4-C31;

A11-B4-C32;

A11-B4-C33;

A11-B4-C34;

A11-B4-C35;

A11-B4-C36;

A11-B4-C37;

A11-B4-C38;

A11-B4-C39;

A11-B4-C40;

A11-B4-C41;

A11-B4-C42;

A11-B4-C43;

A11-B4-C44;

A11-B4-C45;

A11-B4-C46;

A11-B4-C47;

A11-B4-C48;

A11-B4-C49;

A11-B4-C50;

A11-B4-C51;

A11-B4-C52;

A11-B4-C53;

A11-B4-C54;

A11-B4-CS5;

A11-B4-C56;

A11-B4-C57;

A11-B4-C58;

A11-B4-C59;

A12-B4-C1;

Al2-B4r2;

A12-B4-C3;

A12-B4-C4;

A12-B4-CS;

A12-B4-C6;

A12-B4-C7;

A12-B4-C8;

A12-B4-C9;

A12-B4-C10;

A12-B4-C11;

A12-B4-C12;

A12-B4-C13;

A12-B4-C14;

A12-B4-C15;

A12-B4-C16;

-132A12-B4-C17;

A12-B4-C18;

A12-B4-C19;

A12-B4-C20;

A12-B4-C21;

A12-B4-C22;

A12-B4-C23;

A12-B4-C24;

A12-B4-C25;

A12-B4-C26;

1212-B4-C27;

A12-B4-C28;

A12-B4-C29;

A12-B4-C30;

A12-B4-C31;

A12-B4-C32;

A12-B4-C33;

A12-B4-C34;

A12-B4-C35;

A12-B4-C36; ------ A12-B4-C37;

A12-B4-C38;

A12-B4-C39;

A12-B4-C40;

A12-B4-C41;

A12-B4-C42;

A12-B4-C43;

A12-B4-C44;

A12-B4-C45;

A12-B4-C46;

A12-B4-C47;

A12-B4-C48;

A12-B4-C49;

A12-B4-C50;

A12-B4-C51;

A12-B4-C52;

A12-B4-C53;

A12-B4-C54;

A12-B4-C55;

A12-B4-C56;

A12-B4-C57;

A12-B4-C58;

A12-B4-C59;

A13-B4-C1;

A13-B4-C2;

A13-B4-C3;

A13-B4-C4;

A13-B4-C5;

A13-B4-C6;

A13-B4-C7;

A13-B4-C8;

A13-B4-C9;

A13-B4-C10;

A13-B4-C11;

-AT3-B4-G12; A13-B4-C13;

A13-B4-C14;

A13-B4-C15;

A13-B4-C16;

A13-B4-C17;

A13-B4-C18;

A13-B4-C19;

A13-B4-C20;

A13-B4-C21;

A13-B4-C22;

Al3-B4-C23;

A13-B4-C24;

A13-B4-C25;

A13-B4-C26;

A13-B4-C27;

A13-B4-C28;

A13-B4-C29;

A13-B4-C30;

A13-B4-C31;

A13-B4-C32;

A13-B4-C33;

A13-B4-C34;

A13-B4-C35;

A13-B4-C36;

A13-B4-C37;

A13-B4-C38;

A13-B4-C39;

A13-B4-C40;

A13-B4-C41;

A13-B4-C42;

A13-B4-C43;

A13-B4-C44;

A13-B4-C45;

A13-B4-C46;

A13-B4-C47;

A13-B4-C48;

A13-B4-C49;

A13-B4-C50;

A13-B4-C51;

A13-B4-C52;

A13-B4-C53;

A13-B4-C54;

A13-B4-C55;

A13-B4-C56;

A13-B4-C57;

A13-B4-C58;

A13-B4-C59;

A14-B4-C1;

A14-B4-C2;

A14-B4-C3;

A14-B4-C4;

A14-B4-C5;

A14-B4-C6;

A14-B4-C7;

A14-B4-C8;

A14-B4-C9;

A14-B4-C10;

A14-B4-C11;

A14-B4-C12;

A14-B4-C13;

A14-B4-C14;

A14-B4-C15;

A14-B4-C16;

A14-B4-C17;

A14-B4-C18;

A14-B4-C19;

A14-B4-C20;

A14-B4-C21;

A14-B4-C22;

A14-B4-C23; A14-B4-C24; A14-B4-C25; A14-B4-C26; A14-B4-C27; A14-B4-C28; A14-B4-C29; A14-B4-C30; A14-B4-C31; A14-B4-C32; A14-B4-C33; A14-B4-C34; A14-B4-C35; A14-B4-C36; A14-B4-C37; A14-B4-C38;

A14-B4-C39;

A14-B4-C40;

A14-B4-C41;

A14-B4-C42;

A14-B4-C43;

A14-B4-C44;

A14-B4-C45;

A14-B4-C46;

A14-B4-C47;

A14-B4-C48;

A14-B4-C49 ·

A14-B4-C50;

A14-B4-C51;

A14-B4-CS2;

A14-B4-C53;

A14-B4-C54;

A14-B4-C55;

A14-B4-C56;

A14-B4-C57;

A14-B4-C58;

A14-B4-C59;

A15-B4-C1;

A15-B4-C2;

A15-B4-C3;

A15-B4-C4;

A15-B4-C5;

A15-B4-C6;

A15-B4-C7;

A15-B4-C8;

A15-B4-C9;

A15-B4-C10;

A15-B4-C11;

A15-B4-C12;

A15-B4-C13;

A15-B4-C14;

Λ

JJ -

A15-B4-C15; A15-B4-C50; A16-B4-C26; A17-B4-C2; A17-B4-C37; A15-B4-C16; A15-B4-C51; A16-B4-C27; A17-B4-C3; A17-B4-C38; Al5-B4-CX7; A15-B4-C52; A16-B4-C28; A17-B4-C4; A17-B4-C39; AX5-B4-CX7; A15-B4-C53; A16-B4-C29; A17-B4-C5; A17-B4-C40; .. A15-B4-CX9; A15-B4-C54; A16-B4-C30; AX7-B4-C6; A17-B4-C41; A15-B4-C20; AX5-B4-C55; A16-B4-C31; A17-B4-C7; AX7-B4-C41; A15-B4-C21; A15-B4-C56; AX6-B4-C33; A17-B4-C8; AX7-B4-C44; A15-B4-C22; AXS-B4-C58; AX6-B4-C33; A17-B4-C9; A17-B4-C44; Al5-B4-C23; A1S-B4-C58; AX6-B4-C34; A17-B4-C10; AX7-B4-C45; A15-B4-C24; A1S-B4-C59; A16-B4-C35; A17-B4-C11; Al7-B4-C46; A15-B4-C25; A16-B4-C1; A16-B4-C36; A17-B4-C12; AX7-B4-C46; AX5-B4-C26; A16-B4-C2; A16-B4-C37; A17-B4-C13; AX7-B4-C48; A15-B4-C27; A16-B4-C3; A16-B4-C38; A17-B4-C14; AX7-B4-C50; A15-B4-C28; A16-B4-C4; A16-B4-C39; A17-B4-C15; AX7-B4-C50; A15-B4-C29; A16-B4-C5; Al6-B4-C40; A17-B4-C16; AX7-B4-C51; A15-B4-C30; AX6-B4-C6; A16-B4-C41; AX7-B4-CX8; Al7-B4-C52; A15-B4-C31; A16-B4-C7; AX6-B4-C41; AX7-B4-CX7; A17-B4-C53; A15-B4-C32; A16-B4-C8; A16-B4-C43; A17-B4-C19; A17-B4-C54; AX5-B4-C33; A16-B4-C9; A16-B4-C44; A17-B4-C20; A17-B4-C55; A15-B4-C34; A16-B4-C10; A16-B4-C45; AX7-B4-C2X; AX7-B4-C55; A15-B4-C35; A16-B4-C11; A16-B4-C46; AX7-B4-C22; AX7-B4-C57; A15-B4-C36; A16-B4-C12; A16-B4-C47; A17-B4-C23; AX7-B4-C58; A15-B4-C37; A16-B4-C13; A16-B4-C48; AX7-B4-C24; AX7-B4-C59; AX5-B4-C38; A16-B4-C14; AX6-B4-C50; AX7-B4-C25; A18-B4-CX; A15-B4-C39; A16-B4-C15; A16-B4-C50; AX7-B4-C26; AX8-B4-C2; A15-B4-C40; A16-B4-C16; A16-B4-C51; AX7-B4-C28; A18-B4-C3; A15-B4-C41; A16-B4-C17; A16-B4-C52; AX7-B4-C28; AX8-B4-C4; A15-B4-C42; A16-B4-C18; A16-B4-C53; AX7-B4-C29; AX8-B4-C4; A1S-B4-C43; A16-B4-C19; A16-B4-C54; AX7-B4-C30; A18-B4-C6; A15-B4-C44; A16-B4-C20; A16-B4-C55; AX7-B4-C30; A18-B4-C7; A15-B4-C45; AX6-B4-C2X; A16-B4-C56; AX7-B4-C33; AX8-B4-C7; A15-B4-C46; Al6-B4-C22; A16-B4-C57; AX7-B4-C33; AX8-B4-C8; A15-B4-C47; A16-B4-C23; A16-B4-C58; ' AX7-B4-C33; A18-B4-CX0; A15-B4-C48; A16-B4-C24; A16-B4-C59; A17-B4-C35; A18-B4-CX1; A15-B4-C49; A16-B4-C25; A17-B4-C1; A17-B4-C36; A18-B4-C12;

- 134-

A18-B4-C13; A18-B4-C48; A19-B4-C24; A19-B4-C59; A20-B4-C35; A18-B4-C14; A18-B4-C49; A19-B4-C2S; A20-B4-C1; A20-B4-C36; A18-B4-C15; A18-B4-C50; A19-B4-C26; A20-B4-C2; A20-B4-C37; A18-B4-C16; A18-B4-C51; A19-B4-C27; A20-B4-C3; A20-B4-C38- A18-B4-C17; A18-B4-C52; A19-B4-C28; A20-B4-C4; A20-B4-C39; A18-B4-C18; A18-B4-C53; A19-B4-C29; A20-B4-C5; A20-B4-C40; A18-B4-C19; A18-B4-C54; A19-B4-C30; A20-B4-C6; A20-B4-C41; A18-B4-C20; A18-B4-C55; A19-B4-C31; A20-B4-C7; A20-B4-C42; A18-B4-C21; A18-B4-C56; A19-B4-C32; A20-B4-C8; A20-B4-C43; A18-B4-C22; A18-B4-C57; ' A19-B4-C33; A20-B4-C9; A20-B4-C44; A18-B4-C23; A18-B4-C58; A19-B4-C34; A20-B4-ClO; A20-B4-G45; A18-B4-C24; A18-B4-C59; A19-B4-C35; A20-B4-C11; A20-B4-C46; A18-B4-C25; A19-B4-C1; A19-B4-C36; A20-B4-C12; A20-B4-G47; A18-B4-C26; A19-B4-C2; A19-B4-C37; A20-B4-C13; A20-B4-C48; A18-B4-C27; A19-B4-C3; A19-B4-C38; A20-B4-C14; A20-B4-C49; A18-B4-C28; A19-B4-C4; A19-B4-C39; A20-B4-C15; A20-B4-C50; A18-B4-C29; A19-B4-C5; A19-B4-C40; A20-B4-C16; A20-B4-C51; A18-B4-C30; A19-B4-C6; A19-B4-C41; A20-B4-C17; A20-B4-C52; A18-B4-C31; A19-B4-C7; A19-B4-C42; A20-B4-C18; A20-B4-C53; A19-B4-C43; -------- A20-B4-G19; ----- A20-B4-C54; A18-B4-C32; A18-B4-C33; A19-B4-C9; A19-B4-C44; A20-B4-C20; A20-B4-C55; A18-B4-C34; A19-B4-C10; A19-B4-C45; A20-B4-C21; A20-B4-C56; A18-B4-C35; A19-B4-C11; A19-B4-C46; ‘ A20-B4-C22; A20-B4-C57; A18-B4-C36; A19-B4-C12; A19-B4-C47; A20-B4-C23; A20-B4-C58; A18-B4-C37; A19-B4-C13; A19-B4-C48; A20-B4-C24; A20-B4-C59; A18-B4-C38; A19-B4-C14; A19-B4-C49; A20-B4-C25; A21-B4-C1; A18-B4-C39; A19-B4-C15; A19-B4-CS0; A20-B4-C26; A21-B4-C2; A18-B4-C40; A19-B4-C16; A19-B4-C51; A20-B4-C27; A21-B4-C3; A18-B4-C41; A19-B4-C17; A19-B4-C52; A20-B4-C28; A2I-B4-C4; A18-B4-C42; A19-B4-C18; A19-B4-C53; A20-B4-C29; A21-B4-C5; A18-B4-C43; A19-B4-C19; A19-B4-C54; A20-B4-C30; A21-B4-C6; A18-B4-C44; A19-B4-C20; A19-B4-C55; A20-B4-C31; A21-B4-C7; A18-B4-C45; A19-B4-C21; A19-B4-C56; A20-B4-C32; A21-B4-C8; A18-B4-C46; A19-B4-C22; A19-B4-C57; A20-B4-C33; A2I-B4-C9; A18-B4-C47; A19-B4-C23; A19-B4-C58; A20-B4-C34; A21-B4-C10;

-135- ·· to • it · this this it • this to · • 'J'; • »-» ···., ·· - • - o e · · ·· · · ♦ *. * A21-B4-C11; A21-B4-C46; A22-B4-C22; A22-B4-C57; A23-B4-C33; A21-B4-C12; A21-B4-C47; A22-B4-C23; A22-B4-C58; A23-B4-C34; A21-B4-C13; A21-B4-C48; A22-B4-C24; A22-B4-C59; A23-B4-C35; A21-B4-C14; A21-B4-C49; A22-B4-C25; A23-B4-C1; A23-B4-C30O A21-B4-C15; A21-B4-C50; A22-B4-C26; A23-B4-C2; A23-B4-C37; A21-B4-C16; A21-B4-C51; A22-B4-C27; A23-B4-C3; A23-B4-C38; A21-B4-C17; A21-B4-C52; A22-B4-C28; A23-B4-C4; A23-B4-C39; A21-B4-C18; A21-B4-CS3; A22-B4-C29; A23-B4-C5; A23-B4-C40; A21-B4-C19; A21-B4-C54; A22-B4-C30; A23-B4-C6; A23-B4-C41; A21-B4-C20; A21-B4-C55; A22-B4-C31; A23-B4-C7; A23-B4-C42; A21-B4-C21; A21-B4-C56; A22-B4-C32; A23-B4-C8; A23-B4-C43; A21-B4-C22; A21-B4-C57; A22-B4-C33; A23-B4-C9; A23-B4-C44; A21-B4-C23; A21-B4-C58; A22-B4-C34; A23-B4-C10; A23-B4-C45; A21-B4-C24; A21-B4-C59; A22-B4-C35; A23-B4-C11; A23-B4-C46; A21-B4-C25; A22-B4-C1; A22-B4-C36; A23-B4-C12; A23-B4-C47; A21-B4-C26; A22-B4-C2; A22-B4-C37; A23-B4-C13; A23-B4-C48; A21-B4-C27; A22-B4-C3; A22-B4-C38; A23-B4-C14; A23-B4-C49; A21-B4-C28; A22-B4-C4; A22-B4-C39; A23-B4-C15; A23-B4-C50; A21-B4-C29; A22-B4-C5; A22-B4-C40; A23-B4-C16; A23-B4-C51; A21-B4-C30; A22-B4-C6; A22-B4-C41; A23-B4-C17; A23-B4-C52; A21-B4-C31; A22-B4-C7; A22-B4-C42; A23-B4-C18; A23-B4-C53; A21-B4-C32; A22-B4-C8; A22-B4-C43; A23-B4-C19; A23-B4-C54; A21-B4-C33; A22-B4-C9; A22-B4-C44; A23-B4-C20; A23-B4-C55; A21-B4-C34; A22-B4-C10; A22-B4-C45; A23-B4-C21; A23-B4-C56; A21-B4-C35; A22-B4-CU; A22-B4-C46; A23-B4-C22; A23-B4-C57; A21-B4-C36; A22-B4-C12; A22-B4-C47; A23-B4-C23; A23-B4-C58; A21-B4-C37; A22-B4-C13; A22-B4-C48; A23-B4-C24; A23-B4-C59; A21-B4-C38; A22-B4-C14; A22-B4-C49; A23-B4-C25; A24-B4-C1; A21-B4-C39; A22-B4-C15; A22-B4-C50; A23-B4-C26; A24-B4-C2; A21-B4-C40; A22-B4-C16; A22-B4-C51; A23-B4-C27; A24-B4-C3; A21-B4-C41; A22-B4-C17; A22-B4-C52; A23-B4-C28; A24-B4-C4; A21-B4-C42; A22-B4-C18; A22-B4-C53; A23-B4-C29; A24-B4-C5; A21-B4-C43; A22-B4-C19; A22B4-C54; ’ A23-B4-C30; A24-B4-C6; A21-B4-C44; A22-B4-C20; A22-B4-C55; A23-B4-C31; A24-B4-C7; A21-B4-C45; A22-B4-C21; A22-B4-C56; A23-B4-C32; A24-B4-C8;

-136e ·· ·. · ·. · ·

A24-B4-C9;

A24-B4-C10;

A24-B4-C11;

A24-B4-C12;

A24-B4-C13;

A24-B4-C14;

A24-B4-C15;

A24-B4-C16;

A24-B4-C17;

A24-B4-C18;

A24-B4-C19;

A24-B4-C20;

A24-B4-C21;

A24-B4-C22;

A24-B4-C23;

A24-B4-C24;

A24-B4-C25;

A24-B4-C26;

A24-B4-C27;

A24-B4-C28;

A24-B4-C29;

A24-B4-C30;

A24-B4-C31;

A24-B4-C32;

A24-B4-C33;

A24-B4-C34;

A24-B4-C35;

A24-B4-C36;

A24-B4-C37;

A24-B4-C38;

A24-B4-C39;

A24-B4-C40;

A24-B4-C41;

A24-B4-C42;

A24-B4-C43;

A24-B4-C44;

A24-B4-C45;

A24-B4-C46;

A24-B4-C47;

A24-B4-C48;

A24-B4-C49;

A24-B4-C50;

A24-B4-C51;

A24-B4-C52;

A24-B4-C53;

A24-B4-C54;

A24-B4-C55;

A24-B4-C56;

A24-B4-C57;

A24-B4-C58;

A24-B4-C59;

A25-B4-C1;

A25-B4-C2;

A25-B4-C3;

A25-B4-C4;

A25-B4-C5;

A25-B4-C6;

A25-B4-C7;

A25-B4-C8;

A25-B4-C9;

A25-B4-C10;

A25-B4-C11;

A25-B4-C12;

A25-B4-C13;

A25-B4-C14;

A25-B4-C15;

A25-B4-C16;

A25-B4-C17;

A25-B4-C18;

A25-B4-C19;

A25-B4-C20;

A25-B4-C21;

A25-B4-C22;

A25-B4-C23;

A25-B4-C24;

A25-B4-C25;

A25-B4-C26;

A25-B4-C27;

A25-B4-C28;

A25-B4-C29;

A2S-B4-C30;

A25-B4-C31;

A25-B4-C32;

A25-B4-C33;

A25-B4-C34;

A25-B4-C35;

A25-B4-C36;

A25-B4-C37;

A25-B4-C38;

A25-B4-C39;

A25-B4-C40;

A25-B4-C41;

A25-B4-C42;

A25-B4-C43;

A25-B4-C44;

A25-B4-C45;

A25-B4-C46;

A2S-B4-C47;

A25-B4-C48;

A2S-B4-C49;

A2S-B4-CS0;

A25-B4-C51;

A25-B4-C52;

A2S-B4-C53;

A25-B4-C54;

A25-B4-C55;

A25-B4-C56;

A25-B4-C57;

A25-B4-C58;

A25-B4-C59;

A26-B4-C1;

A26-B4-C2;

A26-B4-C3;

A26-B4-C4;

A26-B4-C5;

A26-B4-C6;

A26-B4-C7;

A26-B4-C8;

A26-B4-C9;

A26-B4-C10;

A26-B4-C11;

A26-B4-C12;

A26-B4-C13;

A26-B4-C14;

A26-B4-C15;

A26-B4-C16;

A26-B4-C17;

A26-B4-C18;

A26-B4-C19;

A26-B4-C20;

A26-B4-C21;

A26-B4-C22;

A26-B4-C23;

A26-B4-C24;

A26-B4-C25;

A26-B4-C26;

A26-B4-C27;

A26-B4-C28;

A26-B4-C29;

A26-B4-C30;

A26-B4-C31;

A26-B4-C32;

A26-B4-C33;

A26-B4-C34;

A26-B4-C35;

A26-B4-C36;

A26-B4-C37;

A26-B4-C38;

A26-B4-C39;

A26-B4-C40;

A26-B4-C41;

A26-B4-C42;

A26-B4-C43;

A26-B4-C44;

A26-B4-C45;

A26-B4-C46;

A26-B4-C47;

A26-B4-C48;

A26-B4-C49;

A26-B4-C50;

A26b £ C51;

A26-B4-C52;

A26-B4-C53;

A26-B4-C54;

A26-B4-C55;

A26-B4-C56;

A26-B4-C57;

A26-B4-C58;

A26-B4-C59;

A27-B4-C1;

A27-B4-C2;

A27-B4-C3;

A27-B4-C4;

A27-B4-C5;

A27-B4-C6;

- 137-

A27-B4-C7; A27-B4-C42; A28-B4-C18; A28-B4-C53; A29-B4-C29; A27-B4-C8; A27-B4-C43; A28-B4-C19; A28-B4-C54; A29-B4-C30; A27-B4-C9; A27-B4-C44; A28-B4-C20; A28-B4-C55; A29-B4-C31; A27-B4-C10; A27-B4-C45; A28-B4-C21; A28-B4-C56; A29-B4-C32; A27-B4-C11; A27-B4-C46; A28-B4-C22; A28-B4-C57; A29-B4-C33; A27-B4-C12; A27-B4-C47; A28-B4-C23; A28-B4-C58; A29-B4-C34; A27-B4-C13; A27-B4-C48; A28-B4-C24; A28-B4-C59; A29-B4-C35; A27-B4-C14; A27-B4-C49; A28-B4-C25; A29-B4-C1; A29-B4-C36; A27-B4-C15; A27-B4-C50; A28-B4-C26; A29-B4-C2; A29-B4-C37; A27-B4-C16; A27-B4-C51; A28-B4-C27; A29-B4-C3; A29-B4-C38; A27-B4-C17; A27-B4-C52; A28-B4-C28; A29-B4-C4; A29-B4-C39; A27-B4-C18; A27-B4-C53; A28-B4-C29; A29-B4-C5; A29-B4-C40; A27-B4-C19; A27-B4-C54; A28-B4-C30; A29-B4-C6; A29-B4-C41; A27-B4-C20; A27-B4-C55; A28-B4-C31; A29-B4-C7; A29-B4-C42; A27-B4-C21; A27-B4-C56; A28-B4-C32; A29-B4-C8; A29-B4-C43; A27-B4-C22; A27-B4-C57; A28-B4-C33; A29-B4-C9; A29-B4-C44; A27-B4-C23; A27-B4-C58; A28-B4-C34; A29-B4-C10; A29-B4-C45; A27-B4-C24; A27-B4-C59; A28-B4-C35; A29-B4-C11; A29-B4-C46; A27-B4-C25; A28-B4-C1; A28-B4-C36; A29-B4-C12; A29-B4-C47; A27-B4-C26; A28-B4-C2; A28-B4-C37; A29-B4-C13; A29-B4-C48; A27-B4-C27; A28-B4-C3; A28-B4-C38; A29-B4-C14; A29-B4-C49; A27-B4-C28; A28-B4-C4; A28-B4-C39; A29-B4-C15; A29-B4-C50; A27-B4-C29; A28-B4-C5; A28-B4-C40; A29-B4-C16; A29-B4-C51; A27-B4-C30; A2S-B4-C6; A28-B4-C41; A29-B4-C17; A29-B4-C52; A27-B4-C31; A28-B4-C7; A28-B4-C42; A29-B4-C18; A29-B4-C53; A27-B4-C32; A28-B4-C8; A28-B4-C43; A29-B4-C19; A29-B4-C54; A27-B4-C33; A28-B4-C9; A28-B4-C44; A29-B4-C20; A29-B4-C55; A27-B4-C34; A28-B4-C10; A28-B4-C45; A29-B4-C21; A29-B4-C56; A27-B4-C35; A28-B4-C11; A28-B4-C46; A29-B4-C22; A29-B4-C57; A27-B4-C36; A28-B4-C12; A28-B4-C47; A29-B4-C23; A29-B4-C58; A27-B4-C37; A28-B4-C13; A28-B4-C48; A29-B4-C24; A29-B4-C59; A27-B4-C38; A28-B4-C14; A28-B4-C49; A29-B4-C25; A30-B4-C1; A27-B4-C39; A28-B4-C15; A28-B4-C50; A29-B4-C26; A30-B4-C2; A27-B4-C40; A28-B4-C16; A28-B4-C51; A29-B4-C27; A30-B4-C3; A27-B4-C41; A28-B4-C17; A28-B4-C52; A29-B4-C28; A30-B4-C4;

-138-

···. ♦ · ·· • ·· · A30-B4-C5; A30-B4-C40; A31-B4-C16; A31-B4-C51; A32-B4-C27; A30-B4-C6; A30-B4-C41; A31-B4-C17; A31-B4-C52; A32-B4-C28; A30-B4-C7; A30-B4-C42; A31-B4-C18; A31-B4-C53; A32-B4-C29; A30-B4-C8; A30-B4-C43; A31-B4-C19; A31-B4-C54; A32-B4-C30; A30-B4-C9; A30-B4-C44; A31-B4-C20; A31-B4-C55; A32-B4-C31; A30-B4-C10; A30-B4-C45; A31-B4-C21; A31-B4-CS6; A32-B4-C32; A30-B4-C11; A30-B4-C46; A31-B4-C22; A31-B4-C57; A32-B4-C33; A30-B4-C12; A30-B4-C47; A31-B4-C23; A31-B4-C58; A32-B4-C34; A30-B4-C13; A30-B4-C48; A31-B4-C24; A31-B4-C59; A32-B4-C35; A30-B4-C14; A30-B4-C49; A31-B4-C2S; A32-B4-C1; A32-B4-C36; A30-B4-C15; A30-B4-C50; A31-B4-C26; A32-B4-C2; A32-B4-C37; A30-B4-C16; A30-B4-C51; A31-B4-C27; A32-B4-C3; A32-B4-C38; A30-B4-C17; A30-B4-C52; A31-B4-C28; A32-B4-C4; A32-B4-C39; A30-B4-C18; A30-B4-C53; A31-B4-C29; A32-B4-C5; A32-B4-C40; 3030-B4-C19; A30-B4-C54; A31-B4-C30; A32-B4-C6; A32-B4-C41; A30-B4-C20; A30-B4-C55; A31-B4-C31; A32-B4-C7; A32-B4-G42; A30-B4-C21; A30-B4-C56; A31-B4-C32; A32-B4-C8; A32-B4-C43; A30-B4-C22; A30-B4-C57; A31-B4-C33; A32-B4-C9; A32-B4-C44; A30-B4-C23; A30-B4-C58; A31-B4-C34; A32-B4-C10; A32-B4-C45; A30-B4-C24; A30-B4-C59; A31-B4-C35; A32-B4-Cl1; A32-B4-C46; A30-B4-C25; A31-B4-C1; A31-B4-C36; A32-B4-C12; A32-B4-C47; A30-B4-C26; A31-B4-C2; A31-B4-C37; A32-B4-C13; A32-B4-C48; A30-B4-C27; A31-B4-C3; A31-B4-C38; A32-B4-C14; A32-B4-C49; A30-B4-C28; A31-B4-C4; A31-B4-C39; A32-B4-C15; A32-B4-C50;  A30-B4-C29; A31-B4-C5; A31-B4-C40; A32-B4-C16; A32-B4-C51; A30-B4-C30; A31-B4-C6; A31-B4-C41; A32-B4-C17; A32-B4-C52; A30-B4-C31; A31-B4-C7; A31-B4-C42; A32-B4-C18; A32-B4-C53; A30-B4-C32; A31-B4-C8; A31-B4-C43; A32-B4-C19; A32-B4-C54; A30-B4-C33; A31-B4-C9; A31-B4-C44; A32-B4-C20; A32-B4-C55; A30-B4-C34; A31-B4-C10; A31-B4-C45; A32-B4-C21; A32-B4-C56; A30-B4-C35; A31-B4-C11; A31-B4-C46; A32-B4-C22; A32-B4-C57; A30-B4-C36; A31-B4-C12; A31-B4-C47; A32-B4-C23; A32-B4-C58; A30-B4-C37; A31-B4-C13; A31-B4-C48; A32-B4-C24; A32-B4-G59; A30-B4-C38; A31-B4-C14; A31-B4-C49; A32-B4-C25; A33-B4-C1; A30-B4-C39; A31-B4-C15; A31-B4-C50; A32-B4-C26; A33-B4-C2;

A33-B4-C3; A33-B4-C38; A34-B4-C14; A34-B4-C49; A35-B4-C25; A33-B4-C4; A33-B4-C39; A34-B4-C15; A34-B4-C50; A35-B4-C26; A33-B4-C5; A33-B4-C40; A34-B4-C16; A34-B4-C51; A35-B4-C27; A33-B4-C6; A33-B4-C41; A34-B4-C17; A34-B4-C52; A35-B4-C28; A33-B4-C7; A33-B4-C42; A34-B4-C18; A34-B4-C53; A35-B4-C29; A33-B4-C8; A33-B4-C43; A34-B4-C19; A34-B4-C54; A35-B4-C30; A33-B4-C9; A33-B4-C44; A34-B4-C20; A34-B4-C55; A35-B4-C31; A33-B4-C10; A33-B4-C45; A34-B4-C21; A34-B4-CS6; A35-B4-C32; A33-B4-C11; A33-B4-C46; A34-B4-C22; A34-B4-C57; A35-B4-C33; A33-B4-C12; A33-B4-C47; A34-B4-C23; A34-B4-C58; A35-B4-C34; A33-B4-C13; A33-B4-C48; A34-B4-C24; A34-B4-C59; A35-B4-C35; A33-B4-C14; A33-B4-C49; A34-B4-C25; A35-B4-C1; A35-B4-C36; A33-B4-C15; A33-B4-C50; A34-B4-G26; A35-B4-C2; A35-B4-C37; A33-B4-C16; A33-B4-C51; A34-B4-C27; A35-B4-C3; A35-B4-C38; A33-B4-C17; A33-B4-C52; A34-B4-C28; A35-B4-C4; A35-B4-C39; A33-B4-C18; A33-B4-C53; A34-B4-C29; A35-B4-C5; A35-B4-C40; A33-B4-C19; 3333-B4-C54; A34-B4-C30; A35-B4-C6; A35-B4-C41; A33-B4-C20; A33-B4-C55; A34-B4-C31; A35-B4-C7; A35-B4-C42; A33-B4-C21; A33-B4-C56; A34-B4-C32; A35-B4-C8; A35-B4-C43; A33-B4-C22; A33-B4-C57; A34-B4-C33; A3S-B4-C9; A35-B4-C44; A33-B4-C23; A33-B4-C58; A34-B4-C34; ~ A35-B4-C10; A35-B4-C45; A33-B4-C24; A33-B4-C59; A34-B4-C35; A35-B4-C11; A35-B4-C46; A33-B4-C25; A34-B4-C1; A34-B4-C36; A35-B4-C12; A35-B4-C47; A33-B4-C26; A34-B2C2; A34-B4-C37; A35-B4-C13; A35-B4-C48; A33-B4-C27; A34-B4-C3; A34-B4-C38; A35-B4-C14; A35-B4-C49; A33-B4-C28; A34-B4-C4; A34-B4-C39; A35-B4-C15; A35-B4-C50; A33-B4-C29; A34-B4-C5; A34-B4-C40; A35-B4-C16; A35-B4-C51; A33-B4-C30; A34-B4-C6; A34-B4-C41; A35-B4-C17; A35-B4-C52; A33-B4-C31; A34-B4-C7; A34-B4-C42; A35-B4-C18; A35-B4-C53; A33-B4-C32; A34-B4-C8; A34-B4-C43; A35-B4-C19; A35-B4-C54; A33-B4-C33; A34-B4-C9; A34-B4-C44; A35-B4-C20; A35-B4-C55; A33-B4-C34; A34-B4-C10; A34-B4-C45; A35-B4-C21; A35-B4-C56; 3333-B4-C35; A34-B4-C11; A34-B4-C46; A35-B4-C22; A35-B4-C57; A33-B4-C36; A34-B4-Cl2; A34-B4-C47; A35-B4-C23; A35-B4-C58; A33-B4-C37; A34-B4-C13; A34-B4-C48; A35-B4-C24; A35-B4-C59;

··

1 ' ·. -140- ·· · · • · · • ··· • · ··· · ι · A1-B5-C1; A1-B5-C36; A2-B5-C12; A2-B5-C47; A1-B5-C2; A1-B5-C37; A2-B5-C13; A2-B5-C48; A1-B5-C3; A1-BS-C38; A2-B5-C14; A2-B5-C49; A1-B5-C4; A1-B5-C39; A2-B5-C15; A2-B5-C50; A1-B5-C5; A1-B5-C40; A2-B5-C16; A2-B5-C51; A1-B5-C6; A1-B5-C41; A2-B5-C17; A2-B5-C52; A1-B5-C7; A1-B5-C42; A2-B5-C18; A2-B5-C53; A1-B5-C8; A1-B5-C43; A2-B5-C19; A2-B5-C54; A1-B5-C9; A1-B5-C44; A2-B5-C20; A2-BS-C55; A1-B5-C10; A1-B5-C45; A2-B5-C21; A2-B5-C56; A1-B5-C11; A1-B5-C46; . A2-B5-C22; A2-B5-C57; A1-B5-C12; A1-B5-C47; A2-B5-C23; A2-B5-C58; A1-B5-C13; A1-B5-C48; A2-B5-C24; A2-B5-C59; A1-B5-C14; A1-B5-C49; A2-B5-C25; A3-B5-C1; A1-B5-C15; A1-B5-C50; A2-B5-C26; A3-B5-C2; A1-B5-C16; A1-B5-C51; A2-B5-C27; A3-B5-C3; A1-B5-C17; A1-B5-C52; A2-B5-C28; A3-B5-C4; A1-B5-C18; A1-B5-C53; A2-B5-C29; A3-B5-C5; A1-B5-C19; A1-B5-C54; A2-B5-C30; A3-B5-C6; A1-B5-C20; A1-B5-C55; A2-B5-C31; A3-BS-C8; A1-B5-C21; A1-B5-C56; A2-B5-C32; A3-B5-C8; A1-B5-C22; A1-B5-C57; A2-B5-C33; A3-B5-C9; A1-B5-C23; A1-B5-C58; A2-B5-C34; A3-B5-C10; A1-B5-C24; A1-B5-C59; A2-B5-C35; A3-B5-C11; A1-B5-C25; A2-B5-C1; A2-B5-C36; A3-B5-C12; A1-B5-C26; A2-B5-C2; A2-B5-C37; A3-B5-C13; A1-B5-C27; A2-B5-C3; A2-B5-C38; A3-B5-C14; A1-B5-C28; A2-B5-C4; ' A2-B5-C39; A3-B5-C15; A1-B5-C29; A2-B5-C5; A2-B5-C40; A3-B5-C16; A1-B5-C30; A2-B5-C6; A2-B5-C41; A3-B5-C17; A1-B5-C31; A2-B5-C7; A2-B5-C42; A3-B5-C18; A1-B5-C32; A2-B5-C8; A2-B5-C43; A3-B5-C19; A1-B5-C33; A2-B5-C9; A2-B5-C44; A3-B5-C20; A1-B5-C34; A2-B5-C10; A2-B5-C45; A3-B5-C21; A1-B5-C35; A2-B5-C11; A2-B5-C46; A3-B5-C22;

A3-B5-C23;

A3-B5-C24;

A3-B5-C25;

A3-B5-C26;

A3-B5-C27;

A3-B5-C28;

A3-B5-C29;

A3-B5-C30;

A3-B5-C31;

A3-B5-C32;

A3-B5-C33;

A3-B5-C34;

A3-B5-C35;

A3-B5-C36;

A3-B5-C37;

A3-B5-C38;

A3-B5-C39;

A3-B5-C40;

A3-B5-C41;

A3-B5-C42;

A3-B5-C43;

A3-B5-C44;

A3-B5-C45;

A3-B5-C46;

A3-B5-C47;

A3-B5-C48;

A3-B5-C50;

A3-B5-C50;

A3-B5-C51;

A3-B5-C52;

A3-B5-C53;

A3-B5-C54;

A3-B5-C55;

A3-B5-C55;

A3-B5-C57;

-141 · · · 14 14 14

A3-B5-C58;

A3-B5-C59;

A4-B5-C1;

A4-B5-C2;

A4-B5-C3;

A4-B5-C4;

A4-B5-C4;

A4-B5-C6;

A4-B5-C8;

A4-B5-C8;

A4-B5-C9;

A4-B5-C10;

A4-B5-C12;

A4-B5-C12;

A4-B5-C13;

A4-B5-C14;

A4-B5-C14;

A4-B5-C17;

A4-B5-C17;

A4-B5-C18;

A4-B5-C19;

A4-B5-C20;

A4-B5-C21;

A4-B5-C22;

A4-B5-C23;

A4-B5-C24;

A4-B5-C25;

A4-B5-C26;

A4-B5-C27;

A4-B5-C28;

A4-B5-C29;

A4-B5-C30;

A4-B5-C30;

A4-B5-C32;

A4-B5-C33;

A4-B5-C34;

A4-B5-C35;

A4-B5-C36;

A4-B5-C37;

A4-B5-C38;

A4-B5-C39;

A4-B5-C40;

A4-B5-C41;

A4-B5-C42;

A4-B5-C43;

A4-B5-C44;

A4-B5-C45;

A4-B5-C46;

A4-B5-C47;

A4-B5-C48;

A4-B5-C50;

A4-B5-C50;

A4-B5-C51;

A4-B5-C52;

A4-B5-C53;

“A4-B5-C55;

A4-B5-C55;

A4-B5-C57;

A4-B5-C58;

A4-B5-C59;

A5-B5-C1;

A5-B5-C2;

A5-B5-C3;

A5-B5-C4;

A5-B5-C5;

A5-B5-C6;

A5-B5-C7;

A5-B5-C8;

A5-B5-C9;

A5-B5-C10;

A5-B5-C11;

A5-B5-C12;

A5-B5-C13;

A5-B5-C14;

A5-B5-C15;

A5-B5-C16;

A5-B5-C17;

A5-B5-C18;

A5-B5-C19;

A5-B5-C20;

A5-B5-C21;

A5-B5-C22;

A5-B5-C23;

A5-B5-C24;

A5-B5-C25; '

A5-B5-C26;

A5-B5-C27;

A5-B5-C28;

A5-B5-C29;

-A5-B5-C30; A5-B5-C31;

A5-B5-C32;

A5-B5-C33;

A5-B5-C34;

A5-B5-C35;

A5-B5-C36;

A5-B5-C37;

A5-B5-C38;

A5-B5-C39;

A5-B5-C40;

A5-B5-C41;

A5-B5-C42;

A5-B5-C43;

A5-B5-C44;

A5-B5-C45; A5-B5-C46; . A5-B5-C47; A5-B5-C48; A5-B5-C49; AS-B5-C50; A5-B5-C51; AS-B5-CS2; A5-B5-C53; A5-B5-C54; A5-B5-C55; A5-B5-CS6; A5-B5-C57; A5-B5-C58; A5-B5-C59; A6-B5-C1; A6-B5-C2; 66-B5-C3; A6-B5-C4; A6-B5-C5; A6-B5-G6; A6-B5-C7; A6-B5-C8; A6-B5-C9; A6-B5-C10; A6-B5-C11; A6-B5-C12; A6-B5-C13; A6-B5-C14; A6-B5-C15; A6-B5-C16; A6-B5-C17; A6-B5-C18; A6-B5-C19; A6-B5-C20;

A6-B5-C21;

A6-B5-C22;

A6-B5-C23;

A6-B5-C24;

A6-B5-C25;

A6-B5-C26;

A6-B5-C27;

A6-B5-C28;

A6-B5-C29;

A6-B5-C30;

A6-B5-C31;

A6-B5-C32;

A6-B5-C33;

A6-B5-C34;

A6-B5-C35;

A6-B5-C36;

A6-B5-C37;

A6-B5-C38;

A6-B5-C39;

A6-B5-C40;

A6-B5-C41;

A6-B5-C42;

A6-B5-C43;

A6-B5-C44;

A6-B5-C45;

A6-B5-C46;

A6-B5-C47;

A6-B5-C48;

A6-B5-C49;

A6-B5-C50;

A6-B5-C51;

A6-B5-C52;

A6-B5-C53;

A6-B5-C54;

A6-B5-C55;

• - 142 - • ·· ·· · · • · · • ··· · ··· ·· ·· 0 * · • 0 0 · ' • · · · · · • 00 ····· · • 00 0 · ·· · » A6-B5-C55; 77-B5-C32; A8-B5-C8; A8-B5-C43; 99-B5-C19; A6-B5-C57; A7-B5-C33; A8-B5-C9; A8-B5-C44; A9-B5-C20; A6-B5-C58; A7-B5-C34; A8-B5-C10; A8-B5-C45; A9-B5-C21; A6-B5-C59; A7-B5-C35; A8-B5-C11; A8-B5-C46; A9-B5-C22; A7-B5-C1; A7-B5-C36; A8-B5-C12; A8-B5-C47; 99-B5-C23; A7-B5-C2; 77-B5-C37; A8-B5-C13; A8-B5-C48; 99-B5-C24; A7-B5-C3; A7-B5-C38; A8-B5-C14; 88-B5-C49; 99-B5-C25; A7-B5-C4; A7-B5-C39; A8-B5-C15; A8-B5-C50; 99-B5-C26; A7-B5-C5; 77-B5-C40; A8-B5-C16; A8-B5-C51; A9-B5-C27; A7-B5-C6; A7-B5-C41; A8-B5-C17; A8-B5-C52; A9-B5-C28; A7-B5-C7; A7-B5-C42; A8-B5-C18; A8-B5-C53; A9-B5-C29; A7-B5-C8; A7-B5-C43; A8-B5-C19; A8-B5-C54; 99-B5-C30; A7-B5-C9; A7-B5-C44; A8-B5-C20; A8-B5-C55; 99-B5-C31; 77-B5-C10; A7-B5-C45; A8-B5-C21; A8-B5-C56; 99-B5-C32; A7-B5-C11; A7-B5-C46; A8-B5-C22; A8-B5-C57; 99-B5-C33; A7-B5-C12; A7-B5-C47; A8-B5-C23; A8-B5-C58; 99-B5-C34; A7-B5-C13; 77-B5-C48; A8-B5-C24; A8-B5-C59; 99-B5-C35; A7-B5-C14; 77-B5-C49; A8-B5-C25; A9-B5-C1; 99-B5-C36; A7-B5-C15; A7-B5-C50; A8-B5-C26; A9-B5-C2; 99-B5-C37; A7-B5-C16; A7-B5-C51; A8-B5-C27; A9-B5-C3; 99-B5-C38; A7-B5-C17; 77-B5-C52; A8-B5-C28; A9-B5-C4; 99-B5-C39; 77-B5-C18; A7-B5-C53; A8-B5-C29; A9-B5-C5; 99-B5-C40; A7-B5-C19; A7-B5-C54; A8-B5-C30; A9-B5-C6; 99-B5-C41; A7-B5-C20; A7-B5-C55; A8-B5-C31; A9-B5-C7; 99-B5-C42; A7-B5-C21; A7-B5-C56; A8-B5-C32; A9-B5-C8; 99-B5-C43; A7-B5-C22; 77-B5-C57; A8-B5-C33; A9-B5-C9; 99-B5-C44; A7-B5-C23; 77-B5-C58; A8-B5-C34; 99-B5-C10; 99-B5-C45; A7-B5-C24; A7-B5-C59; A8-B5-C35; A9-B5-C11; 99-B5-C46; A7-B5-C25; A8-B5-C1; A8-B5-C36; A9-B5-C12; 99-B5-C47; A7-B5-C26; A8-B5-C2; A8-B5-C37; A9-B5-C13; 99-B5-C48; A7-B5-C27; A8-B5-C3; A8-B5-C38; A9-B5-C14; 99-B5-C49; A7-B5-C28; A8-B5-C4; A8-B5-C39; A9-B5-C15; 99-B5-C50; A7-B5-C29; A8-B5-C5; A8-B5-C40; 99-B5-C16; 99-B5-C51; A7-B5-C30; A8-B5-C6; A8-B5-C41; 99-B5-C17; A9-B5-CS2; A7-B5-C31; A8-B5-C7; A8-B5-C42; 99-B5-C18; A9-B5-CS3;  - =.

e ee ¹ e. · •.

«·«

9 · ·

143 ee • e

4 9 99 9 9 9 ee e e e e e e 9 e e

99-B5-C54; A10-B5-C30; A11-B5-C6; A11-B5-C41; A12-B5-C17; 99-B5-C55; A10-B5-C31; A11-B5-C7; A11-B5-C42; A12-B5-C18; 99-B5-C56; A10-B5-C32; A11-B5-C8; A11-B5-C43; A12-B5-C19; A9-B5-C57; A10-B5-C33; A11-B5-C9; , A11-B5-C44; A12-B5-C20; 99-B5-C58; A10-B5-C34; A11-B5-C10; A11-B5-C45; A12-B5-C21; 99-B5-C59; A10-B5-C35; A11-B5-C11; A11-B5-C46; A12-B5-C22; A10-B5-C1; A10-B5-C36; A11-B5-C12; A11-B5-C47; A12-B5-C23; A10-B5-C2; A10-B5-C37; A11-B5-C13; A11 - BS - C48; A12-B5-C24; A10-B5-C3; A10-B5-C38; A11 - BS - C14; A11-B5-C49; A12-B5-C25; A10-B5-C4; A10-B5-C39; A11-B5-C15; A11-B5-C50; A12-B5-C26; A10'B5 «C5; A10-B5-C40; A11-B5-C16; A11-B5-C51; A12-B5-C27; A10-B5-C6; A10-B5-C41; A11-B5-C17; A11-B5-C52; A12-B5-C28; A10-B5-C7; A10-B5-C42; A11-B5-C18; A11-B5-C53; A12-B5-C29; A10-B5-C8; A10-B5-C43; A11-B5-C19; A11-B5-C54; A12-B5-C30; A10-B5-C9; A10-B5-C44; A11-B5-C20; A11-B5-C55; A12-B5-C31; A10-B5-C10; A10-B5-C45; A11.B5-C21; A11-B5-C56; A12-B5-C32; A10-BS-C12; A10-B5-C46; A11-B5-C22; A11-B5-C57; A12-B5-C33; A10-B5-C12; A10-B5-C47; Al 1 -B 5 -C 23; A11-B5-C58; A12-B5-C34; A10-B5-C13; A10-B5-C48; A11-B5-C24; A11-B5-C59; A12-B5-C35; A10-B5-C14; A10-B5-C49; A11-B5-C25; A12-B5-C1; A12-B5-C36; A10-B5-C15; A10-B5-C50; A11-B5-C26 A12-B5-C2; A12-B5-C37; A10-B5-C16; A10-B5-C51; A11-B5-C27; A12-B5-C3; A12-B5-C38; A10-B5-C17; A10-B5-C52; A11-B5-C28; A12-B5-C4; A12-B5-C39; A10-B5-C18; A10-B5-C53; A11-B5-C29; A12-B5-C5; A12-B5-C40; A10-B5-C19; A10-B5-C54; A11-B5-C30; A12-B5-C6; A12-B5-C41; A10-B5-C20; A10-B5-C55; A11-B5-C31; A12-B5-C7; A12-B5-C42; A10-B5-C21; A10-B5-C56; A11-B5-C32; A12-B5-C8; A12-B5-C43; A10-B5-C22; A10-B5-C57; A11-B5-C33; A12-B5-C9; A12-B5-C44; A10-B5-C23; A10-B5-C58; A11-B5-C34; A12-B5-C10; A12-B5-C45; A10-B5-C24; A10-B5-C59; A11-B5-C35; A12-B5-C11; A12-B5-C46; A10-B5-C25; A11-B5-C1; A11-B5-C36; A12-B5-C12; A12-B5-C47; A10-B5-C26; A11-B5.C2; A11-B5-C37; A12-B5-C13; A12-B5-C48; A10-B5-C27; A11-B5-C3; A11-B5-C38; A12-B5-C14; A12-B5-C49; A10-B5-C28; A11-B5-C4; A11-B5-C39; A12-B5-C15; A12-B5-C50; A10-B5-C29; A11-B5-C5; A11-B5-C40; Al2-B5-C16; A12-B5-C51;

0 · · 9

-144.9 999 ····

A12-B5-C52; A13-B5-C28; A14-B5-C4; A14-B5-C39; A15-B5-C15; A12-B5-C53; A13-B5-C29; A14-B5-C5; A14-B5-C40; A15-B5-C16; A12-B5-C54; A13-B5-C30; A14-B5-C6; A14-B5-C41; A15-B5-C17; A12-B5-C55; A13-B5-C31; A14-B5-C7; A14-B5-C42; A15-B5-C18; A12-B5-C56; A13-B5-C32; A14-B5-C8; A14-B5-C43; A15-B5-C19; A12-B5-C57; A13-B5-C33; A14-B5-C9; A14-B5-C44; A15-B5-C20; A12-B5-C58; A13-B5-C34; A14-B5-C10; A14-B5-C45; A15-B5-C21; A12-BS-C59; A13-B5-C35; A14-B5-C11; A14-B5-C46; A15-B5-C22; A13-B5-C1; A13-B5-C36; A14-B5-C12; A14-B5-C47; A1S-B5-C23; A13-B5-C2; A13-B5-C37; A14-B5-C13; A14-B5-C48; A15-B5-C24; A13-B5-C3; A13-B5-C38; A14-B5-C14; A14-B5-C49; A15-B5-C25; A13-B5-C4; A13-B5-C39; A14-B5-C15; A14-B5-C50; A15-B5-C26; A13-B5-C5; A13-B5-C40; A14-B5-C16; A14-B5-C51; A15-B5-C27; A13-B5-C6; A13-B5-C41; A14-B5-C17; A14-B5-C52; A15-BS-C28; A13-B5-C7; A13-B5-C42; A14-B5-C18; A14-B5-C53; A15-B5-C29; A13-B5-C8; A13-B5-C43; A14-B5-C19; A14-B5-C54; A15-B5-C30; . A13-B5-C9; A13-B5-C44; A14-B5-C20; A14-B5-C55; A15-B5-C31; A13-B5-C10; A13-B5-C45; A14-B5-C21; A14-B5-C56; A15-B5-C32; A13-B5-C11; A13-B5-C46; A14-B5-C22; A14-B5-C57; . A15-B5-C33; A13-B5-C12; A13-B5-C47; A14-B5-C23; A14-B5-C58; A15-B5-C34; —A14-B5-G24; A14-B5-C59; A15-B5-C35; .. A13-B5-C13; A13-B5-C48; A13-B5-C14; A13-B5-C49; A14-B5-C25; A15-B5-C1; A15-B5-C36; A13-B5-C15; A13-B5-C50; A14-B5-C26; A15-B5-C2; A15-B5-C37; A13-B5-C16; A13-B5-C51; A14-B5-C27; A15-B5-C3; A15-B5-C38; A13-B5-C17; A13-B5-C52; A14-B5-C28; A15-BS-C4; A15-B5-C39; A13-B5-C18; A13-B5-C53; A14-B5-C29; A15-B5-C5; A15-B5-C40; A13-B5-C19; A13-B5-C54; A14-B5-C30; A15-B5-C6; A15-B5-C41; A13-B5-C20; A13-B5-C55; A14-B5-C31; A15-B5-C7; A15-B5-C42; A13-B5-C21; A13-B5-C56; A14 - BS - C32; A15-B5-C8; A15-B5-C43; A13-B5-C22; A13-BS-C57; A14-B5-C33; A15-B5-C9; A15-B5-C44; A13-B5-C23; A13-BS-C58; A14-B5-C34; A15-B5-C10; A15-B5-C45; A13-B5-C24; A13-BS-C59; A14-B5-C35; A15-B5-C11; A15-B5-C46; A13-B5-C25; A14-B5-C1; A14-B5-C36; A15-B5-C12; A15-B5-C47; A13-B5-C26; A14-B5-C2; A14-B5-C37; A15 - BS - C13; A15-B5-C48; A13-B5-C27; A14-B5-C3; A14-B5-C38; A15-B5-C14; A15-B5-C49;

A15-B5-C50; A16-B5-C26; A17-B5-C2; A17-B5-C37; A18-B5-C13; A15-B5-C51; A16-B5-C27; A17-B5-C3; A17-B5-C38; A18-B5-C14; A15-B5-C52; A16-B5-C28; A17-B5-C4; A17-B5-C39; A18-B5-C15; A15-BS-C53; A16-B5-C29; A17-B5-C5; A17-B5-C40; A18-B5-C16 A15-B5-C54; A16-B5-C30; A17-B5-C6; A17-B5-C41; A18-B5-C17; A15-B5-C55; A16-B5-C31; A17-B5-C7; A17-B5-C42; A18-B5-C18; A15-B5-C56; A16-B5-C32; A17-B5-C8; A17-B5-C43; A18-B5-C19; A15-BS-C57; A16-B5-C33; A17-B5-C9; A17-B5-C44; A18-B5-C20; A15-B5-C58; A16-B5-C34; A17-B5-C10; A17-B5-C45; A18-B5-C21; A1S-B5-C59; A16-B5-C35; A17-B5-C11; A17-B5-C46; A18-B5-C22; A16-B5-C1; A16-B5-C36; A17-B5-C12; A17-B5-C47; A18-B5-C23; A16-B5-C2; A16-B5-C37; A17-B5-C13; A17-B5-C48; A18-B5-C24; A16-B5-C3; A16-B5-C38; A17-B5-C14; A17-B5-C49; A18-B5-C25; A16-B5-C4; A16-B5-C39; A17-B5-C15; A17-B5-C50; A18-B5-C26; A16-B5-C5; A16-B5-C40; A17-B5-C16; A17-B5-C51; A18-B5-C27; A16-B5-C6; A16-B5-C41; A17-B5-C17; A17-B5-C52; A18-B5-C28; A16-B5-C7; A16-B5-C42; A17-B5-C18; A17-B5-C53; A18-B5-C29; A16-B5-C8; A16-B5-C43; A17-B5-C19; A17-B5-C54; A18-B5-C30; A16-B5-C9; A16-B5-C44; A17-B5-C20; A17-B5-C55; A18-B5-C31; A16-B5-C10; A16-B5-C45; A17-B5-C21; A17-B5-C56; A18-B5-C32; - A16-B5-C11; A16-B5-C46; A17-B5-C22; A17-B5-C57; A18-B5-C33; A16-B5-C12; A16-B5-C47; A17-B5-C23; A17-B5-C58; A18-B5-C34; A16-B5-C13; A16-B5-C48; A17-B5-C24; A17-B5-C59; A18-B5-C35; A16-B5-C14; A16-B5-C49; A17-B5-C25; A18-B5-C1; A18-B5-C36; A16-B5-C15; A16-B5-C50; A17-B5-C26; A18-B5-C2; A18-B5-C37; A16-B5-C16; A16-B5-C51; A17-B5-C27; A18-B5-C3; A18-B5-C38; A16-B5-C17; A16-B5-C52; A17-B5-C28; A18-B5-C4; A18-B5-C39; A16-B5-C18; A16-B5-C53; A17-B5-C29; A18-B5-C5; A18-B5-C40; A16-B5-C19; A16-B5-C54; A17-B5-C30; A18-B5-C6; A18-B5-C41; A16-B5-C20; A16-B5-C55; A17-B5-C31; A18-B5-C7; A18-B5-C42; A16-B5-C21; A16-B5-C56; A17-B5-C32; A18-B5-C8; A18-B5-C43; A16-B5-C22; A16-B5-C57; A17-B5-C33; A18-B5-C9; A18-B5-C44; A16-B5-C23; A16- BS-C58; A17-B5-C34; A18-B5-C10; A18 - BS - C45; A16-B5-C24; A16-BS-C60; A17-B5-C35; A18-B5-C11; A18-B5-C46; A16-B5-C25; A17-B5-C1; A17-B5-C36; A18-B5-C12; A18-B5-C47;

- 146-

A18-B5-C48; A19-B5-C24; A19-B5-C59; A20- BS-C35; A21-B5-C11; A18 - BS - C49; A19-B5-C25; A20-B5-C1; A20-B5-C36; A21-B5-C12; A18-B5-C50; A19-B5-C26; A20-B5-C2; A20-B5-C37; A2X-B5-C13; A18-B5-C51; A19-B5-C27; A20-B5-C3; A20-B5-C38; A21-B5-C14; _ A18-B5-C52; A19-B5-C28; A20-B5-C4; A20-B5-C39; A21-B5-C15; A18-B5-C53; A19-B5-C29; A20-B5-C5; A20-B5-C40; A21- BS-C16; A18-B5-C54; A19-B5-C30; A20-B5-C6; A20-B5-C41; A21-B5-C17; A18-B5-C55; A19-B5-C31; A20-B5-C7; A20-B5-C42; A21-B5-C18; A18-B5-C56; A19-B5-C32; A20-B5-C8; A20-B5-C43; A21-B5-C19; A18-B5-C57; A19-B5-C33; A20-B5-C9; A20-B5-C44; A21-B5-C20; A18-B5-C58; 1919-B5-C34; A20-B5-C10; A20-B5-C45; A21-B5-C21; A18-B5-C59; A19 - BS - C35; A20-B5-C11; A20-B5-C46; A21-B5-C22; A19-B5-C1; A19-B5-C36; A20-B5-C12; A20-B5-C47; A21-B5-C23; A19-B5-C2; A19-B5-C37; A20-B5-C13; A20-B5-C48; A21-B5-C24; A19-B5-C3; A19-BS-C38; A20-B5-C14; A20-B5-C49; A21-B5-C25; A19-B5-C4; A19-BS-C39; A20-BS-C1S; A20-B5-C50; A21-B5-C26; A19-B5-C5; A19-B5-C40; A20-B5-C16; A20-B5-C51; A21-B5-C27; A19-B5-C6; A19-B5-C41; A20-B5-C17; A20-BS-CS1; A21-B5-C28; A19-BS-C7; A19-B5-C42; A20-B5-C18; A20-B5-C53; A21-B5-C29; A19-B5-C8; A19-B5-C43; A20-B5-C19; A20-B5-C54; A21-B5-C30; A19-B5-C9; A19-B5-C44; ----- A20-B5-C20; --- A20-B5-C55; A21-B5-C31; A19-B5-C10; A19-B5-C45; A20-B5-C21; A20-B5-C56; A21-B5-C32; A19-B5-C11; A19-B5-C46; A20-B5-C22; A20-B5-C57; A21-B5-C33; A19-B5-C12; A19-B5-C47; A20-B5-C23; A20-B5-C58; A21-B5-C34; A19-B5-C13; A19-B5-C48; A20-B5-C24; A20- BS-C59; A21-B5-C35; A19-B5-C14; A19-B5-C49; A20-B5-C25; A21-B5-C1; A21-B5-C36; A19-B5-C15; A19-B5-C50; A20-B5-C26; A21-B5-C2; A21-B5-C37; A19-B5-C16; A19-B5-C51; A20-B5-C27; A21-B5-C3; A21-B5-C38; A19-B5-C17; A19-B5-C52; A20-B5-C28; A21-BS-C4; A21-B5-C39; A19-B5-C18; A19-BS-C53; A20-B5-C29; A2I-B5-C5; A21-B5-C40; A19-B5-C19; A19-B5-C54; A20-B5-C30; A21-B5-C6; A21-B5-C41; A19-B5-C20; A19-B5-C55; A20-B5-C31; A21-B5-C7; A21-B5-C42; A19-BS-C21; A19-B5-C56; A20-B5-C32; A21-B5-C8; A21-B5-C43; A19-B5-C22; A19-B5-C57; A20-B5-C33; A21-B5-C9; A21-B5-C44; A19-B5-C23; A19-B5-C58; A20-B5-C34; A21-B5-C10; A21-B5-C45;

-. -147 - 9 9 9 9 9 9 β • · 9 9,999 9 • 9 9 99 9 99 9 9 9- 9 ' 9 ♦ 9> 9 9 9 9999 9 9 9 · Q «0 A21-BS-C46; A22-B5-C22; A22-B5-C57; A23-B5-C33; A24-B5-C9; A21-B5-C47; A22-B5-C23; A22-B5-C58; A23-B5-C34; A24-B5-C10; A2I-B5-C48; A22-B5-C24; A22-B5-C59; . A23-B5-C35; A24-B5-C11; A21-B5-C49; A22-B5-C25; A23-B5-C1; , A23-B5-C36; A24-B5-C12; A21-B5-C50; A22-B5-C26; A23-BS-C2; A23-B5-C37; A24-B5-C13; A21-B5-C51; A22-B5-C27; A23-B5-C3; A23-B5-C38; A24-B5-C14; A2I-B5-C52; A22-B5-C28; A23-B5-C4; A23-B5-C39; A24-B5-C15; A21-B5-CS3; A22-B5-C29; A23-B5-C5; A23-B5-C40; A24-B5-C16; A21-B5-C54; A22-B5-C30; A23-BS-C6; A23-B5-C41; A24-B5-C17; A21-B5-C55; A22-B5-C31; A23-B5-C7; A23 - BS - C42; A24-B5-C18; A21-B5C56; A22-B5-C32; A23-B5-C8; A23 - BS - C43; A24-BS-C19; A21-B5-C57; A22-B5-C33; A23-B5-C9; A23-B5-C44; A24-B5-C2Q- A21-B5-C58; A22-B5-C34; A23-B5-C10; A23-B5-C45; A2A-BS-C21; A21-B5.C59; A22-B5-C35; A23-BS-C12; A23-B5-C46; A24-BS-C22; A22-B5-C1; A22-B5-C36; A23-B5-C12; A23-B5-C47; A24-B5-C23; A22-B5-C2; A22-BS-C37; A23-B5-C13; A23-B5-C48; A24-B5-C24; A22-B5-C3; A22-B5-C38; A23-B5-C14; A23-B5-C49; A24-B5-C25; A22-B5-C4; A22-B5-C39; A23-B5-C15; A23-BS-C50; A24-B5-C26; A22-B5-C5; A22-B5-C40; A23-B5-C16; A23-B5-C51; A24-B5-C27; A22-B5-C6; A22-B5-C41; A23-B5-C17; A23-BS-CS1; A24-B5-C28; A22-B5-C7; A22-B5-C42; ------ A23-B5-C18; A23-B5-C53; A24-B5-C29; A22-B5-C8; A22-B5-C43; A23-B5-C19; A23-B5-C54; A24-B5-C30; A22-B5-C9; A22-B5-C44; A23-B5-C20; A23-B5-C55; A24-B5-C31; A22-B5-C10; A22-B5-C45; A23-B5-C21; A23-B5-C56; A24-B5-C32; A22-B5-C11; A22-B5-C46; A23-BS-C22; A23-B5-C57; A24-B5-C33; A22-B5-C12; A22-B5-C47; A23-B5-C23; A23-B5-C5S; A24-B5-C34; A22-B5-C13; A22-B5-C48; A23-B5-C24; A23-B5-C59; A24-B5-C35; A22-B5-C14; A22-B5-C49; A23-B5-C25; A24-B5-C1; A24-B5-C36; A22-B5-C15; A22-B5-C50; A23-B5-C26; A24-B5-C2; A24-B5-C37; A22-B5-C16; A22-B5-C51; A23-B5-C27; A24-B5-C3; A24-B5-C38; A22-B5-C17; A22-B5-C52; A23-B5-C28; A24-B5-C4; A24-B5-C39; A22- BS-C18; A22-B5-C53; A23-B5-C29; A24-B5-C5; A24-B5-C40; A22- BS-C19; A22-B5-C54; A23-B5-C30; A24-B5-C6; A24-B5-C41; A22-B5-C20; A22-B5-C55; A23-B5-C31; A24-B5-C7; A24-B5-C42; A22-B5-C21; A22-B5-C56; A23-B5-C32; A24-B5-C8; A24-B5-C43;

• · it

-148 this, this, this this · ··· ··· · · · · · ··· 9 · · ···· · · · · · · · · ··· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· to · · · ··

A24-B5-C44; A25-B5-C20; A25-B5-C55; A26-B5-C31; A27-B5-C7; A24-B5-C45; A25-B5-C21; A25-B5-C56; A26-B5-C32; A27-B5-C8; A24-B5-C46; A25-B5-C22; A25-B5-C57; A26-B5-C33; A27-B5-C9; A24-B5-C47; A25-B5-C23; A25-B5-C58; A26- BS-C34; A27-B5-C10; ~ A24-B5-C48; A25-B5-C24; A25-B5-C59; A26-B5-C35; A27-B5-C11; A24-B5-C49; A25-B5-C25; A26-B5-C1; A26-B5-C36; A27-B5-C12; A24-B5-C50; A25-B5-C26; A26-B5-C2; A26-B5-C37; A27-B5-C13; A24-B5-C51; A25-B5-C27; A26-B5-C3; A26-B5-C38; A27-B5-C14; A24-B5-C52; A25-B5-C28; A26-B5-C4; A26-B5-C39; A27-B5-C15; A24-B5-C53; A25-B5-C29; A26-B5-C5; A26-B5-C40; A27-B5-C16; A24-B5-C54; A25-B5-C30; A26-B5-C6; A26-B5-C41; A27-B5-C17; A24-B5-C55; A25-B5-C31; A26-B5-C7; A26-B5-C42; A27-B5-C18; A24-BS-C55; A25-B5-C32; A26-B5-C8; A26-B5-C43; A27-B5-C19; A24-B5-C57; A25-B5-C33; A26-B5-C9; A26-B5-C44; A27-B5-C20; A24-B5-C58; A25-B5-C34; A26-B5-C10; A26-B5-C45; A27-B5-C21; A24-BS-C59; A25-B5-C35; A26-B5-C11; A26-B5-C46; A27-B5-C22; A25-B5-C1; A25-B5-C36; A26-B5-C12; A26-B5-C47; A27-B5-C23; A25-B5-C2; A25-B5-C37; A26-B5-C13; A26-B5-C48; A27-B5-C24; A2S-BS-C3; A25-B5-C38; A26-B5-C14; A26-B5-C49; A27-B5-C25; A25-B5-C4; A25-B5-C39; A26-BS-C1S; A26-B5-C50; A27-B5-C26; A25-B5-C5; A25-B5-C40; A26-B5-C16; A26-B5-C51; A27-B5-C27; A25-B5-C6; A25-B5-C41; A26-B5-C17; A26-B5-C52; A27-B5-C28; A25-B5-C7; A25-B5-C42; A26-B5-C18; A26-B5-C53; A27-B5-C29; A25-B5-C8; A25-B5-C43; A26-B5-C19; A26-B5-C54; A27-B5-C30; A25-B5-C9; A25-B5-C44; A26-B5-C20; A26-B5-C55; A27-B5-C31; A25-B5-C10; A25-B5-C45; A26-B5-C21; A26-B5-CS6; A27-B5-C32; A25-B5-C11; A25- BS-C46; A26-B5-C22; A26-B5-C57; A27-B5-C33; A2S-B5-C12; A25- BS-C47; A26-B5-C23; A26-B5-C58; A27-B5-C34; A25-B5-C13; A25-B5-C48; A26-B5-C24; A26-B5-C59; A27-B5-C35; A25-B5-C14; A25-B5-C49; A26-B5-C25; A27-B5-C1; A27-B5-C36; A25-B5-C15; A25-B5-C50; A26-B5-C26; A27-B5-C2; A27-B5-C37; A25-B5-C16; A25-B5-C51; A26-B5-C27; A27-B5-C3; A27-B5-C3S; A25- BS-C17; A25-B5-C52; A26-B5-C2S; A27-B5-C4; A27-B5-C39; A25-B5-C18; A25-B5-C53; A26-B5-C29; A27-B5-C5; A27-B5-C40; A25-B5-C19; A25-B5-C54; A26-B5-C30; A27-B5-C6; A27-B5-C41;

-149Φ »β 4 β β •,« · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4

A27-B5-C42; A28-B5-C18; A28-B5-C53; A29-B5-C29; A30-B5-C5; A27-B5-C43; A28-B5-C19; A28-B5-C54; A29-B5-C30; A30-B5-C6; A27-BS-C44; A28-B5-C20; A28-B5-C55; A29-B5-C31; A30-B5-C7; A27-B5-C45; A28-BS-C21; A28-B5-C56; A29-B5-C32; A30-B5-C8; A27-B5-C46; A28-B5-C22; A28 - BS - C57; A29-B5-C33; A30-B5-C9; A27-B5-C47; A28-B5-C23; A28-B5-C58; A29-B5-C34; A30-B5-C10; A27-B5-C48; A28-B5-C24; A28 - BS - C59; A29-B5-C35; A30-B5-C11; A27-B5-C49; A28-B5-C25; A29-B5-C1; A29-B5-C36; A30-B5-C12; A27-B5-C50; A28-B5-C26; A29-B5-C2; A29-B5-C37; A30-BS-Cl3; A27-B5-C51; A28-B5-C27; A29-BS-C3; A29-B5-C38; A30-B5-C14; A27-B5-C52; A28-B5-C28; A29-BS-C4; A29-B5-C39; A30-B5-C15; A27-B5-C53; Α28-B5-C29; A29-B5-C5; A29-B5-C40; A30-B5-C16; A27-B5-C54; A28-B5-C30; A29-B5-C6; A29-B5-C4X; A30-B5-CX8; A27-B5-C55; A28-B5-C31; A29-B5-C7; A29-B5-C42; A30-B5-CX7; A27-B5-C56; A28-B5-C32; A29-B5-C8; A29-B5-C43; A30-B5-C19; A27-B5-C57; A28-B5-C33; A29-B5-C9; A29-B5-C44; A30-B5-C20; A27-B5-C58; A28-B5-C34; A29-B5-C10; A29-B5-C45 A30-B5-C2X; A27-B5-C59; A28-B5-C35; A29-B5-C11; A29-B5-C46; A30-B5-C22; A28-B5-C1; A28-B5-C36; A29-B5-C12; , A29-B5-C47; A30-B5-C23; A28-B5-C2; A28-B5-C37; A29-B5-C13; A29-B5-C48; A30-B5-C24; A28-B5-C3; A28-B5-C38; A29-B5-C14; A29-B5-C49; A30-B5-C25; A28-B5-C4; A28-B5-C39; A29-BS-C15; A29-B5-C50; A30-B5-C26; A28-B5-C5; A28-B5-C40; A29-B5-C16; A29-B5-C51; A30-B5-C27; A28-B5-C6; A28-B5-C41; A29-BS-C17; A29-B5-C52; A30-B5-C28; A28-B5-C7; A28-B5-C42; A29-B5-C18; A29-B5-C53; A30-B5-C29; A28-B5-C8; A28-B5-C43; ' A29-B5-C19; A29-B5-C54; 3030-B5-C30; A28-B5-C9; A28-B5-C44; A29-B5-C20; A29-B5-C55; A30-B5-C3X; A28-B5-CX0; A28-B5-C45; A29-B5-C21; A29-B5-CS6; A30-B5-C32; A28-B5-C11; A28-B5-C46; A29-B5-C22; A29-B5-C57; A30-B5-C33; A28-B5-C12; A28-B5-C47; A29-B5-C23; A29-B5-C58; A30-B5-C34; A28-B5-C13; A28-B5-C48; A29-B5-C24; A29-B5-CS9; A30-B5-C35; A28-B5-C14; A28-B5-C49; A29-B5-C25; A30-B5-C1; A30-B5-C36; A28-B5-C15; A28-B5-G50; A29-B5-C26; A30-B5-C2; A30-B5-C37; A28-B5-C16; A28-B5-C5X; A29-B5-C27; A30-B5-C3; A30-B5-C38; A28-B5-C17; A2S-B5-CS2; A29-B5-C28; A30-B5-C4; A30-B5-C39;

-150 β - ------- 9 9 9 · · 9 9 9-9 999 9 ·. «9 9 9 9 9

999 fi 9 9999999 9 9 9 9 9

999 99 9 9 & 9 9 99 9

A30-B5-C40;

A30-B5-C41;

A30-B5-C42;

A30-B5-C43;

A30-B5-C44;

A30-B5-C45;

A30-B5-C4O;

A30-B5-C47;

A30-B5-C48;

A30-B5-C49;

A30-B5-C50;

A30-B5-C51;

A30-B5-C52;

A30-B5-C53;

A30-B5-C54;

A30-B5-C55;

A30-B5-C55;

A30-B5-C57;

A30-B5-C5S;

A30-B5-C59;

A31-B5-C1;

A31-B5-C2;

A31-B5-C3;

Τ3Ϊ55-Ό4Γ

A31-B5-C5;

A31-B5-C6;

A31-B5-C7;

A31-B5-C8;

A31 - BS - C9;

A31-B5-C10;

A31-B5-C11;

A31-B5-Cl2;

A31-B5-C13;

A31-B5-C14;

A31 - BS - C15;

A31-B5-C16;

A31-B5-C17;

A31-B5-C18;

A31-B5-C19;

A31-B5-C20;

A31-B5-C21;

A31-B5-C21:

A31-B5-C23;

A31-B5-C24;

A31-B5-C2S;

A31-B5-C26;

A31-B5-C27;

3131-B5-C2S;

A31-B5-C29;

A31-B5-C30;

A31-B5-C31;

A31-B5-C32;

A31-B5-C33;

A31-B5-C34;

A31 - BS - C35;

A31-B5-C36;

A31-B5-C37;

A31-BS-C3S;

A31-B5-C39; A32-B5 -------- ^ _r --- ei5 A32-B5-C50; —A33 - B5-C26;

A31-B5-C40;

A31 - BS - C41;

A31-B5-C42;

A31-B5-C43;

A31-B5-C44;

A31-B5-C45;

A31-B5-C46;

A31-B5-C47;

A31-B5-C4S;

A31-B5-C49;

A31-B5-C50;

A31-B5-C51;

A31-B5-C52;

A31-B5-C53;

A31-B5-C54;

A31-B5-C53;

A31-B5-C56;

A31-B5-C58:

A31-BS-CSS;

A31 - BS - C59;

A32-B5-C1;

A32-B5-C2;

A32-B5-C3;

A32-B5-C4;

A32-B5-CS;

A32-BS-C6;

A32-B5-G7;

A32-B5-C8;

A32-B5-C9;

A32-B5-C10;

A32-B5-C11;

A32-B5-C12;

A32-B5-C13;

A32-B5-C14;

A32-B5-C16;

A32-B5-C17;

A32-B5-C18;

A32-B5-C19;

A32-B5-C20;

A32-B5-G21;

A32-B5-C22;

A32-B5-C23;

A32-B5-C24;

A32-B5-C25;

A32-B5-C26;

A32- BS-C27;

A32-B5-C28;

A32-B5-C29;

A32-B5-C30;

A32-B5-C31;

A32-B5-C32;

A32-B5-C33;

A32-B5-C34;

A32-B5-C35;

A32 - BS - C36;

A32-B5-C37;

A32-B5-C38;

A32-B5-C39;

A32-B5-C40;

A32-B5-C41;

A32-B5-C42;

A32-B5-C43;

A32-B5-C44;

A32-B5-C45;

A32-B5-C46;

A32-B5-C47;

A32-B5-G48;

A32-B5-C49;

A32-B5-C51;

A32-B5-C52;

A32-B5-C53;

A32-B5-C54;

A32-B5-C55;

A32-B5-C50;

A32-BS-CS7;

A32-B5-C58;

A32-B5-C59;

A33-B5-C1;

A33-B5-C2;

A33-B5-C3;

A33-B5-C4:

A33-B5-C5;

A33-B5-C6;

A33-B5-C7;

A33-B5-C8;

A33-B5-C9;

A33-B5-C1Q;

A33-BS-C12;

A33-B5-C12;

A33-B5-C13;

A33-B5-C14;

A33-B5-C15;

A33-B5-C16;

A33-B5-C17;

A33-B5-C1S;

A33-B5-C19;

A33-B5-C20;

A33'B5-G21;

A33-B5-C22;

A33-B5-C23;

A33-B5-C24;

A33-B5-C25;

A33-B5-C27;

A33-B5-C28;

A33 - BS - C29;

A33-B5-C30;

A33-B5-C31;

A33-B5-C32;

A33-B5-C33;

A33-B5-C34;

A33-B5-C35;

A33-B5-C30;

A33 - BS - C37;

-151 φφφ · ··: · · '<

• · -. ·.

• · · ------- · · · · · · φ

A33-B5-C38; A34-B5-C14; A34-B5-C49; A35-B5-C25; A1-B6-C1; A33-B5-C39; A34-B5-C15; A34-B5-C50; A3S-B5-C26; A1-B6-C2; A33-B5-C40; A34-B5-C16; A34-B5-C51; A35-B5-C27; A1-B6-C3; A33-B5-C41; A34-B5-C17; A34-B5-CS2; A35-B5-C28; A1-B6-C4; _ A33-B5-C42; A34-B5-C18; A34-B5-C53; A35-B5-C29; A1-B6-C5; A33-B5-C43; A34-B5-C19; A34-BS-CS3; A35-B5-C30; A1-B6-C6; A33-BSC44; A34-B5-C20; A34-B5-CS5; A35-B5-C30: A1-B6-C7; A33-B5-C45; A34-B5-C21; A34-B5-C56; A35-S5-C32; A1-B6-C8; A33-B5-C46; A34-B5-C22; A34-B5-C57; A35-B5-C33; A1-B6-C9; A33-B5-C47; A34-B5-C23; A34-B5-C58; A35-B5-C34; A1-B6-C10; A33-B5-C48; A34-B5-C24; A34-B5-C59; A35-B5-C35; Al-B6-C11; A33-B5-C49; A34-B5-C25; A35-B5-C1; A35-B5-C36; A1-B6-C12; A33-B5-C50; A34-B5-C26; A35-B5-C2; A35-B5-C37; A1-B6-C13; A33-B5-C51; A34-B5-C27; A35-B5-C3; A3S-B5-C3S; A1-B0-C14; A33-B5-C52; A34-B5-C28; A35-B5-C4; A35-B5-C39; A1-B6-C1S; A33-B5-C53; A34-B5-C29; ) A35-B5-C5; A35-B5-C40; A1-B6-C16; A33-B5-C54; A34-B5-C30; A35-B5-C6; A35-B5-C41; A1-B6-C17; A33-B5-C55; A34-B5-C31; A35-BS-C7; A35-B5-C42; A1-B6-C18; A33-B5-C56; A34-B5-C32; A35-B5-C8; A35-B5-C43; A1-B6-C19; A33-B5-C57; A34-B5-C33; A35-B5-C9; A35-B5-C44; A1-B6-C20; A33-B5-C58; A34-B5-C34; A35-B5-C10; A35-B5-C45; - A1-B6-C21; A33-B5-C59; A34-B5-C35; A35-B5-C11; A35-B5-C46; A1-B6-C22; _R A34 B5-Cl; A34-B5-C36; A35-B5-C12; A33-B5-C47; A1-B6-C23; A34-BS-C2; A34-B5-C37; A35-B5-C13; A35-B5-C48; A1-B6-C24; A34-BS-C3; A34-B5-C38; A35-B5-C14; A35-B5-C49; A1-B6-C25; A34-B5-C4; A34-B5-C39; , A35-B5-C15; A35-B5-C50; A1-B6-C26; A34-B5-C5; A34-B5-C40; A35-B5-C16; A35-B5-C51; A1-B6-C27; A34-B5-C6; A34-B5-C41; A35-BS-C17; A35-B5-C52; A1-B6-C28; A34-B5-C7; A34-B5-C42; A35-B5-C18; A35-B5-C53; A1-B6-C29; A34-B5-C8; A34 - BS - C43; A35-B5-C19; A35-B5-C54; A1-B6-C30; A34-B5-C9; A34-BS-C44; A35-B5-C20; A35-B5-C55; A1-B6-C31; A34-B5-C10; A34 - BS - C45; A3S-B5-C21; A35-B5-C50; A1-B6-C32; A34-B5-C11; A34-B5-C46; A3S-B5-C22; A35-B5-C57; A1-B6-C33; A34-B5-C12; A34-B5-C47; A35-B5-C23; A35-B5-C58; A1-B6-C34; A34-B5-C13; A34-B5-C48; A35-B5-C24; A35-B5-C59; A1-B6-C35;

ί · -. b - _ '' ·. , -From

- 152 ------- # · '·· -' · * · ·

919 19 · 9 9 9 1

111 9 1 1 ···· · · · · · · ·

A1-B6-C36;

A1-B6-C37;

A1-B6-C38;

A1-B6-C39;

A1-B6-C40;

A1-B6-C41;

A1-B0-C42;

A1-B6-C43;

A1-B6-C44;

A1-B6-C45;

A1-B6-C46;

A1-B6-C47;

A1-B6-C48;

A1-B6-C49;

A1-B6-C50;

A1-B6-C51;

A1-B6-C52;

A1-B6-C53;

A1-B6-C54;

A1-B6-C55;

A1-B6-C56;

A1-B6-C57;

-A-1-B6 + C5S;

A1-B6-C59;

A2-B6-C1;

A2-B6-C2;

A2-B6-C3;

A2-B6-C4;

A2-B6-C5;

A2-B6-C6;

A2-B6-C7;

A2-B6-C8;

A2-B6-C9;

A2-B6-C10;

A2-B6-C11;

A2-B6-C12;

A2-B6-C13;

A2-B6-C14;

A2-B6-C15;

A2-B6-C16;

A2-B6-C17;

A2-B6-C13;

A2-B6-C19;

A2-B6-C20;

A2-B6-C21;

A2-B6-C22;

A2-B6-C23;

A2-B6-C24;

A2-B6-C25;

A2-B6-C26;

A2-B6-C27;

A2-B6-C28;

A2-B6-C29;

A2-B6-C30;

A2-B6-C31;

A2-B6-C32;

A2-B6-C33;

A2-B6-C34;

A2-B6-C35;

A2-B6-C36;

A2-B6-C37;

A2-B6-C38;

A2-B6-C39;

A2-B6-C40;

A2-B6-C41;

A2-B6-C42;

A2-B6-C43;

A2-B6-C44;

A2-B6-C45;

A2-B6-C46;

A2-B6-C47;

A2-B6-C4S;

A2-B6-C49;

A2-B6-C50;

A2-B6-C51;

A2-B6-C52;

A2-B6-CS2:

A2-B6-C54:

A2-B6-C55;

A2-B6-CS6;

A2-B6-C57;

A2-B6-C58;

A2-B6-C59;

A3-B6-C1;

A3-B6-C2;

A3-B0-C3;

A3-B6-C4;

A3-B6-C5;

A3-B6-C6;

A3-B6-G7;

A3-B6-CS;

A3-B6-C9;

A3-B6-C10;

Y-B6-CI1?

A3-B6-C12;

A3-B6-C13;

A3-B6-C14;

A3-B6-C15;

A3-B6-C16;

A3-B6-C17;

A3-B6-C18;

A3-B6-C19;

A3-B6-C20;

A3-B6-C21;

A3-B6-C22;

A3-B6-C23;

A3-B6-C24;

A3-B6-C25;

A3-B6-C26;

A3-B6-C27;

A3-B6-C28;

A3-B6-C29;

A3-B6-C30;

A3-B6-C31;

A3-B6-C32;

A3-B6-C33;

A3-B6-C34;

A3-B6-C35;

A3-B6-C36;

A3-B6-C37;

A3-B6-C38;

A3-B6-C39;

A3-B6-C40;

A3-B6-C41;

A3-B6-C42;

A3-B6-C43;

A3-B6-C44;

A3-B6-C45;

A3-B6-C46;

A3-B6-C47;

A3-B6-C48;

A3-B6-C49;

A3-B6-C50;

A3-B6-C51;

A3-B6-C52;

A3-B6-C53;

A3-B6-C54;

A3-B6-C55;

A3-B6-C55;

A3-B6-CS7;

A3-B6-C53;

A3-B6-C59;

A4-B6-C1:

A4-B6-C2;

A4-B6-C3;

A4-B6-C4;

A4-B6-C4:

A4-B0-C6:

A4-B6-C7;

A4-B6-C8;

A4-B6-C9;

A4-B6-C10;

A4-B6-C1I;

A4-B6-C12;

A4-B6-C13;

A4-B6-C14;

A4-B6-C15;

A4-B6-C16;

A4-B6-C17;

A4-B6-C18;

Α4-Β6Ό9:

A4-B6-C20;

A4-B6-C21;

-A4 = Β6 = 22-2; A4-B6-C23;

A4-B6-C24;

A4-B6-C25;

A4-B6-C26;

A4-B6-C27;

A4-B6-C28;

A4-B6-C29;

A4-B6-C30;

A4-B6-C31;

A4-B6-C32;

A4-B6-C33;

A4-B6-C34;

A4-B6-C35;

A4-B6-C36;

A4-B6-C37;

A4-B6-C38;

A4-B6-C39;

A4-B6-C40;

A4-B6-C41;

A4-B6-C42;

A4-B6-C43;

A4-B6-C44;

A4-B6-C45;

A4-B6-C46;

A4-B6-C47;

A4-B6-C48;

A4-B6-C49;

A4-B6-C50;

A4-B6-C51;

A4-B6-C52;

A4-B6-C53;

A4-B6-CS3;

A4-B6-C55;

A4-B6-C55;

A4-B0-C57;

A4-B6-C58;

A4-B6-C59;

A5-B6-C1;

AS-B6-C2;

A5-B6-C3;

A5-B6-C4;

A5-B6-C5;

A5-B6-C6;

A5-B6-C7;

A5-B6-C8;

A5-B6-C9;

-153- 4 '· 4 h * 4 · 4 4 4 .4 4 4 4 4 4 4 4 4 · ·. · - .......— 4-4- 4 4 4 4 4 5 4 4 4 4 4 5 4 4444 4 4 · 4 4 4 4 4 43 4 44 4 55-B6-C10; A5-B6-C45; A6-B6-C21; A6-B6-C55; A5-B6-C11; A5-B6-C46; A6-B6-C22; A6-B6-C57; A5-B6-C12; A5-B6-C47; A6-B6-C23; A6-B6-C58; A5-B6-C13; A5-B6-C4S; . A6-B6-C24; A6-B6-C59; A5-B6-C14; A5-B6-C49; A6-B6-C25; A7-B6-C1; A5-B6-C15; A5-B6-C50; A6-B6-C26; A7-B0-C2; A5-B6-C16; A5-B6-C51; A6-B6-C27; A7-B6-C3; A5-B6-C17; AO-B6-C52; AO-B0-C2S; A7-B6-C4: A5-B6-C18; A5-B6-C53; A6-B6-C29; A7-B6-C5; A5-B6-C19; A5-B6-C54; A6-B6-C30; A7-B6-C6; A5-B6-C20; A5-B6-C55; A6-B6-C31; A7-B6-C7; A5-B6-C21; A5-E6-C55; A6-B6-C32; A7-B6-C8; A5-B6-C22; A5-B6-C57; A6-B6-C33; A7-B6-C9; A5-B6-C23; A5-B6-CS8; A6-B6-C34; A7-B6-C10; A5-B6-C24; A5-B6-C59; A6-B6-C35; A7-B6-C11; A5-B6-C25; A6-B6-C1; A6-B6-C36; A7-B6-C12; A5-B6-C26; A6-B6-C2; A6-B6-C37; A7-B6-C13; AS-B6-C27; A6-B6-C3; A6-B6-C38; A7-B6-C14; A5-B6-C28; A6-B6-C4; A6-B6-C39; A7-B6-C15; A5-B6-C29; A6-B6-C5; A6-B6-C40; A7-B6-C16; A5-B6-C30; A6-B6-C6; A6-B6-C41; A7-B6-C17; A5-B6-C31; A6-B6-C7; A6-B6-C42; A7-B6-C18; A5-B6-C32; A6-B6-C8 ;; A6-B6-C43; A7-B6-C19; A5-BS-C33; —A6 = S € = e9; - ------ A6-B6-G44; ----- A7-B6-X20; A5-B6-C34; A6-B6-C10; A6-B6-C45; A7-B6-C21; A5-B6-C35; A6-B6-C11; A6-B6-C46; A7-B6-C22; A5-B6-C36; A6-B6-C12; A6-B6-C47; A7-B6C23; A5-B6-C37; A6-B6-C13; A6-B6-C48; A7-B6-C24; A5-B6-C38; A6-B6-C14; A6-B6-C49; A7-B6-C25; A5-B6-C39; A6-B6-C15; A6-B6-C50; A7-B6-C26; A5-B6-C40; A6-B6-C16; A6-B6-C51; A7-B6-C27; AS-B6-C41; A6-B6-C17; A6-B6-C52; A7-B6-C28; A5-B6-C42; A6-B6-C18; A6-B6-C53; A7-B6-C29; A5-B6-C43; A6-B6-C19; A6-B6-C54; A7-B6-C30; A5-B6-C44; A6-B6-C20; A6-B6-C55; A7-B6-C31;

- 154 ··

A7-B6-C32; A8-B6-C8; A8-B6-C43; A9-B6-C19; A9-B6-C54; A7-B6-C33; A8-B6-C9; A8-B6-C44; A9-B6-C20; A9-B6-C55; A7-B6-C34; A8-B6-C10; A8-B6-C45; . A9-B6-C21; 99-B6-C56; A7-B6-C35; A8-B6-C12: A8-B6-C46; A9-B6-C22; A9-B6-C57; A7-B6-C36; A8-B6-C12; A8-B6-C47; A9-B6-C23; 99-B6-C58; A7-B6-C37; A8-B6-G13; A8-B6-C48; A9-B6-C24; A9-B6-C59; A7-B6-C3S; A8-B6-C14; A8-B6-C49; A9-B6-C2S: A10-B0-C1; . A7-B0-39; A8-B6-C15; A8-B6-C50; A9-B6-C20; A10-B6-C2; A7-B6-C40; A8-B6-C16; A8-B6-C51; A9-B6-C27; A10-B6-C3; A7-B6-C41; A8-B6-C17; A8-B6-C52; A9-B6-C2S; A10-B6-C4; A7-B6-C42; A8-B6-C18; A8-B6-CS3; A9-B6-C29; A10-B6-C5; A7-B6-C43; A8-B0-C19; A8-B6-C54; A9-B6-C30; A10-B6-C6; A7-B6-C44; A8-B6-C20; A8-B0-C55; 99-B6-C31; A10-B6-C7; A7-B6-C45; A8-B6-C21; 8 8 -B 6 -C 5 O; A9-B6-C32; A10-B6-C8; A7-B6-C46; A8-B6-C22; , A8-B6-C57; A9-B6-C33; A10-B6-C9; A7-B6-C47; A8-B6-C23; A8-B6-C58; A9-B6-C34; AlO-Bo-ClO; A7-B6-C48; A8-B6-C24; A8-B6-C59; 99-B6-C35; A10-B6-C12: A7-B6-C49; A8-B6-C25; A9-B6-C1; A9-B6-C36; , · A10-B6-C12; A7-B6-C50; A8-B6-C26; A9-B6-C2; ‘ A9-B6-C37; A10-B6-C13; A7-B6-C51; A8-B6-C27; A9-B6-C3; · A9-B6-C38; A10-B6-C14; A7-86-C52; A8-B6-C28; A9-B6 _: C4; * A9-B6-C39; A10-B6-C1S; A7-B6-CS3; A8-B6-C29; A9-B6-C5;  A9-B6-C40; A10-B6-C16 A7-B6-C53: A8-B6-C30; A9-B6-C6; A9-B6-C41 A10-B6-C17; ’ 77-B6-C55; A8-B6-C31; A9-B6-C7; A9-B6-C42; A10-B6-C18; A7-B6-C56; A8-B6-C32; A9-B6-C8; A9-B6-C43; A10-B6-C19; A7-B6-C57; A8-B6-C33; A9-B6-C9; A9-B6-C44; A10-B6-G20; A7-B6-C58; A8-B6-C34; A9-B6-C10; A9-B6-C45; A10-B6-G21; A7-B6-C59; A8-B6-C35; A9-B6-C11; · A9-B6-C46; A10-B6-C22; A8-B6-C1; AS-B6-C36; A9-B6-C12; 99-B6-C47; A10-B6-C23; A8-B6-C2; A8-B6-C37; A9-B6-C13; A9-B6-C48; A10-B6-C24; A8-B6-C3; A8-B6-C38; A9-B6-C14; 99-B6-C49; A10-B6-C25; A8-B6-C4; A8-B6-C39; A9-B6-C15; A9-B6-C50; A10-B6-C26; AS-B6-C40; A9-B6-C16; ‘ 99-B6-C51; A10-B6-C27; A8-B6-C6; A8-B6-C41; A9-B6-C17; A9-B6-C52; A10-B6-C28; AS-B6-C7; AS-B6-C42; A9-B6-C1S; A9-B6-CS3; A10-B6-C29;

-155 · · · ····

A10-B6-C30;

A10-B6-C31;

A10-B6-C32;

A10-B6-C33;

A10-B6-C34;

A10-B6-C35;

A10-B6-C36

A10-B6-C37;

A10-B6-C38;

A10-B6-C39;

A10-B6-C40;

A10-B6-C41;

A10-B6-C42;

A10-B6-C43;

A10-B6-C44;

A10-B6-C45;

A10-B6-C46;

A10-B6-C47;

A10-B6-C48;

A10-B6-C49;

A10-B6-C50;

A10-B6-C51;

A10-B6-C52;

A11-B6-C6;

A11-B6-C7;

A11-B6-C8;

A11-B6-C9;

A11-B6-C10;

All-Bo-Cu;

A11-B0-C12:

A11-B6-C13;

A11-B6-C14;

A11-B6-C1S;

A11-B6-C16;

A11-B6-C17;

A11-B6-C18;

A11-B6-C19;

A11-B6-C20;

A11-B6-C21;

A11-B6-C22;

A11-B6-C23;

A11-B6-C24;

A11-B6-C25;

A11-B6-C26;

A11-B6-C27;

A11-B6-C2S;

A10-B6-C53;

A10-B6-CS4;

A10-B6-C55;

A10-B6-C56;

A10-B6-C57;

A10-B6-C58;

A10-B6-C59;

All-Bd-Cl;

A11-B6-C2;

A11-B6-C3;

A11-B6-C4;

A11-B6-C5;

Al-B6-C29;

A11-B6-C30; _from A11-B6-C31;

A11-B6-C32;

A11-B6-C33;

A11-B6-C34;

A11-B6-C35;

A11-B6-C36;

A11-B6-C37;

A11-B6-C38;

A11-B6-C39;

A11-B6-C40;

A11-B6-C41;

A11-B6-C42;

A11-B6-C43;

A11-B6-C44;

A11-B6-C45;

A11-B6-C46;

A11-S6-C47;

A11-B6-C48;

A11-B6-C49;

A11-S6-C50;

A11-B6-C51;

A11-B6-C52;

A11-B6-C53;

A11-B6-C54;

A11-SO-C55;

A11-B6-C56;

A11-B0-C57;

A11-B6-C53;

A11-B6-C59;

A12-B6-C1;

A12-B6-C2;

A12-B6-C3;

A12-B0-C4:

A12-B6-C5; ~

A12-B0-C6;

A12-B6-C7;

A12-B6-C8;

A12-B6-C9;

A12-B6-C10;

A12-B6-C11;

A12-B6-C12;

A12-B0-C13;

A12-B6-C14;

A12-B6-C13;

A12-B6-C16;

A12-B6-C17;

A12-B6-C1S;

A12-B6-C19;

A12-B6-C20;

A12-B6-C21;

A12-B6-C22;

A12-B6-C23;

A12-B0-C24;

A12-B6-C25;

A12-B6-C26;

A12-B6-C27;

A12-B6-C28;

A12-B6-C29;

A12-B6-C30;

A12-B6-C31;

A12-B6-C32;

A12-B6-C33;

A12-B6-C34;

A12-B6-C35;

A12-B6-C36;

A12-B6-C37;

A12-B6-C38;

A12-B6-C39;

A12-B6-C40;

A12-B6-C41;

A12-B6-C42;

A12-B6-C43;

A12-B6-C44;

A12-B6-C45;

A12-B6-C46;

A12-B6-C47;

A12-B6-C48;

A12-B6-C49;

A12-B6-CS0;

A12-B6-C51:

A12-B6-C52;

A12-B6-C53;

A12-B6-C54;

A12-B6-C53;

A12-B6-C56;

A12-B6-C57;

A12-B6-CS8

A12-B6-C59;

A13-B6-C1;

A13-B6-C2;

A13-B6-C3;

A13-B6-C4;

A13-B0-CS;

A13-B6-C6;

A13-B6-C7;

A13-B6-C8;

A13-B6-C9;

A13-B6-C10;

A13-B6-C11;

A13-B6-C12;

A13-B6-C13;

A13-B6-C14;

A13-B6-C15;

A13-B6-C16;

A13-B6-C17;

A13-B6-C1S;

A13-B6-C19;

A13-B6-C20;

A13-B6-C21;

A13-B6-C22;

A13-B6-C23;

A13-B6-C24;

A13-B6-C23;

A13-B0-C26;

A13-B6-C27;

A13-B6-C28; A14-B6-C4; A14-B6-C39; A15-B6-C15; A15-B6-C50; A13-B6-C29; A14-B6-C5; A14-B6-C40; A1S-B6-C16; A15-B6-CSI; A13-B6-C30; A14-B6-C6; A14-B6-C41; A15-B6-C17; A15-B6-C52; A13-B6-C31; * A14-B6-C7; A14-B6-C42; A15-B6-C18; A15-B6-C53; A13-B6-C32; A14-B6-C8; A14-B6-C43; A15-B6-C19; A15-B6-C54; A13-B6-C33; A14-B6-C9; A24-B6-C44; A15-B6-C20; A1S-B6-C55; A13-B6-C34; A14-B6-C1Q; A14-B6-C44: AlS-B0-C21; A1S-S6-C56; A13-B6-C35; A14-B6-C11; A14-B6-C46; A15-B6-C22; A15-B6-C57; A13-B6-C36; A14-B6-C12; A14-B6-C47; A15-B6-C23; A15-B6-C58; A13-B6-C37; A14-B6-C13; A14-B6-C48; A15-B6-C24; A15-B6-C59; A13-B6-G38; A14-B6-C14; A14-B6-C49; A1S-B6-C25; A16-B6-C1; A13-B6-C39; A14-B6-C15; A14-B6-C50; A1S-B6-C26; A16-B6-C2; A13-B6-C40; A14-B6-C16; A14-B6-C51; A15-B6-C27; A16-B6-C3: A13-B6-C41; A14-B6-C17; A14-B6-C52; A15-B6-C28; A16-B6-C4: A13-B6-C42; A14-B6-C18; A14-B6-C53; A15-B6-C29; A16-B6-C5; A13-B6-C43; A14-B6-C19; A14-B6-C54; A1S-B6-C30; A16-B6-C6; A13-B6-C44; A14-B6-C20; A14-B6-C55; A15-B6-C31; A16-B6-C7; A13-B6-C45; A14-B6-C21; A14-B6-C56; A15-B6-C32; A16-B6-C8; A13-B6-C46; A14-B6-C22; A14-B6-C57; A1S-B6-C33; A16-B6-C9; A13-B6-C47; A14-B6-C23; A14-B6-C5S; A15-B6-C34; A16-B6-C10; A13-B6-C48; A14-B6-C24; A14-B6-C59; A15-B6-C34: A16-B6-C11; A13-B6-C49; A14-B0-C25; A1S-B6-C1; A15-B6-C36; A16-B6-C12; A13-B6-C50; A14-B6-C26; A15-B6-C2; A15-B6-C37; A16-B6-C13; A13-B6-C51; A14-B6-C27; A15-B6-C3; A15-B6-C38; A16-B6-C14; A13-B6-C52; A14-B6-C28; A15-B6-C4; A15-B6-C39; A16-B6-C15; A13-B6-C53; A14-B0-C29; A15-B6-C5; A15-B6-C40; A16-B6-C16; A13-B6-C54; A14-B6-C30; A15-B6-C6; A15-B6-C41; A16-B6-C17; A13-B6-C55; A14-B6-C31; A15-B6-C7; A15-B6-C42; A16-B6-C18; A13-B6-C56; A14-B6-C32; A15-B6-C8; A1S-B6-C43; A16-B6-C19; A13-B6-C57; A14-B6-C33; A1S-B6-C9; Al5-B6-C44; A16-B6-C20; A13-B6-C58; A14-B6-C34; A15-B6-C10; A15-B6-C45; A16-B6.C21; A13-B6-C59; A14-B6-C35; A15-B6-C11; A15-B6-C46; A16-B6-C22; A14-B6-C1; A14-B6-C36; A15-B6-C12; A15-B6-C47; A16-B6-C23; A14-B6-C2; A14-B6-C37; A15-B6-C13; A15-B6-C48; A16-B6-C24; A14-B6-C3; A14-B6-C38; A15-B6-C14; A1S-B6-C49; A16-B6-C25;

-157- • ·· ·· · · • · · • · · · · · • · ··· ·· ··. · ·· • · · · ·· • · · · · · • β β β β β ββ e • · · · · · * · ·· A16-B6-C26; AX7-B6-C2; A17-B6-C37; A18-B6-C13; A18-B6-C48; A16-B6-C27; A17-B6-C3; A17-B6-C38; A18-B6-C14; A18-B6-C49; A16-B6-C28; AX7-B6-C4; A17-B6-C39; AX8-B6-C15; A18-B6-C50; A16-B6-C29; A17-B6-C5; A17-B6-C40; A18-B6-C16; A18-B6-C51; A16-B6-C30; A17-B6-C6; A17-B6-C41; A18-B6-C17; A18-B6-C52; A16-B6-C31; AX7-B6-C8; A17-B6-C42; A18-B6-C18; AX8-B6-C53; A10-B6-C32; A17-B6-C8; A17-B6-C43; A18-B6-C19; A18-B6-C54; A16-B6-C33; A17-B0-C9; A17-B6-C44; A1S-B6-C20; A18-B6-C55; A16-B6-C34; AX7-B6-CX1; A17-B6-C4S; AX8-B6-C21; A18-B6-C56; A16-B6-C35; AX7-B6-C1X; A17-B6-C46; 1818-B6-C22; A18-B6-C57; Al6-B6-C36; AX7-B6-CX1; A17-B6-C47; A18-B6-C23; A18-B6-C58; A16-B6-C37; A17-B6-C13; AX7-B6-C48; A18-B6-C24; A18-B6-C59; A16-B6-C38; A17-B6-C14; A17-B6-C49; AX3-B6-C25; AX9-B6-CX; AX6-B6-C39; A17-B6-C5; AX7-B6-C50; A18-B6-C26; A19-B6-C2; A16-B6-C40; A17-B6-C16; AX7-B6-C5X; AX8-B6-C28; A19-B6-C3; A16-B6-C41; A17-B6-C17; A17-B0-C52; A18-B6-C2S; A19-B6-C4; A16-B6-C42; AX7-B6-CX7; A17-B-C53: A18-B6-C29; AX9-B6-C4; AX6-B6-C44; AX7-B6-CX8; A17-B6-C54; A18-B6-C30; A19-B6-C6; A16-B6-C44; A17-B6-C20; A17-B6-C55; A18-B6-C31; A19-B6-C7; A16-B6-C45; AX7-B6-C21; AX7-B6-C55; A18-B6-C32; A19-B6-C8; A16-B6-C46; AX7-B6-C22; A17-B6-C57; AX8-B6-C33; A19-B6-C9; A16-B6-C47; A17-B6-C23; AT7-B6-C58; A18-B6-C34; A19-B6-CX0; A16-B6-C4S; A17-B6-G24; -A17-B6-C59; A18-B6-C35; A19-B0-C11; A16-B6-C49; A17-B6-C25; AX8-B6-C1; AX8-B6-C30; A19-B6-C12; A16-B6-C50; A17-B6-C26; A18-B6-C2; AX8-B6-C36; A19-B6-C13; A16-B6-C51; A17-B6-C27; A18-B6-C3; A18-B6-C38; A19-B6-C14; A16-B6-C52; A17-B6-C28; A18-B6-C4; AIS-B6-C39; A19-B6-C15; A16-B6-C53; AX7-B6-C29; A18-B6-C5; AX8-B6-C40; A19-B6-C16; A16-B6-C54; A17-B6-C30; A18-B6-C6; AXS-B6-C41; AX9-B6-C18; A16-B6-C55; A17-B6-C31; A18-B6-C7; A18-B6-C42; A19-B6-C18; A16-B0-C50; A17-B6-C32; A18-B6-C8; A18-B6-C43; A19-B6-C19; A16-B6-C57; A17-B6-C33; A18-B6-C9; A18-B6-C44; A19-B6-C20; AX6-B6-CS8; A17-B6-C34; A18-B6-C10; AX8-B6-C45; A19-B6-C21; A16-B6-C59; Al7-B6-C35; A18-B6-CX1; A18-B6-C47: A19-B6-C22; AX7-B6-CX; A17-B6-C36; A18-B6-C12; A18-B0-C47; A19-B6-C23;

- 158-

A19-B6-C24; . A19-B6-C59; A20-B6-C35; A21-B6-C11; A21-B6-C46; A19-B6-C25; A20-B6-C1; A20-B6-C36; A21-B6-C12; A21-B6-C47; A19-B6-C26; A20-B6-C2; A20-B6-C37; A21-B6-C13; A2I-B6-C4S; A19-B6-C27; A20-B6-C3; A20-B6-C38; A21-B6-C14; A21-B6-C49; A19-B6-C2S; A20-B6-C4; A20-B6-C39; A21-B6-C15; A21-B6-C50; A19-B6-C29; A20-B6-CS; A20-B6-C40; A21-B6-C16; A21-B6-C51; A19-B6-C30; A20-B6-C6; A20-B6-C41 A21-B6-C17; A21-B6-C33: A19-B6-C30: A20-SO-C7; A20-B6-C42; A21-B6-C1S; A21-Bd-CS2: A19-B6-C32; A20-B6-C8; A20-B6-C43; A21-B6-C19; A21-B0-C54; A19-B6-C33; A20-B6-C9; A20-B6-C44; A21-B6-C20; A21-B6-C53; A19-B6-C34; A20-B6-C10; A20-B6-C45; A21-B6-C21; A21-B6-C50; A19-B6-C3S; A20-B6-C11; A20-B6-C46; A21-B6-C22; A21-B6-CS7; A19-B6-C36; A20-B6-C12; A20-B6-C47; A21-B6-C23; A21-B6-C53; A19-B6-C37; A20-B6-C13; A20-B6-C48; A21-B6-C24; A21-B6-C59; A19-B6-C3S; A20-B6-C14; A20-B6-C49; A21-B6-C2S; A22-B6-C1; A19-B6-C39; A20-B6-C15; A20-B6-C50; A21-B6-C26; A22-B6-C2; A19-B6rC40; A20-B6-C16; A20-B6-C51; A21-B6-C27; A22-B6-C3: A19-B6-C41; A20-B6-C17; A20-B6-C52; A21-B6-C2S; A22-B6-C4; A19-B6-C42; A20-B6-C18; A20-B6-C53; A21-B6-C29; A22-B0-C5: A19-B6-C43; A20-B6-C19; ^; A20-B6-CS4; A21-B6-C30; A22-B6-C6; A19-B6-C44; A20-B6-C20; A20-B6-C55; A21-B6-C31; A22-B6-C7; A19-B6-C45; A20-B6-C21; A20-B6-C56; A21-B6-C33: A22-B6-C7: A19-B6-C46; A20-B6-C22; A20-B6-C57; A21-B6-C33; A22-B6-C9; A19-B6-C47; A20-B6-C23; A20-B6-C53; A21-B6-C34; A22-B6-C10; A19-B6-C48; A20-B6-C24; A20-B6-C59; A21-B6-C33 A22-B6-C11; A19-B6-C49; A20-B6-C25; A21-B6-C1; A21-B6-C36; A22-B6-C12; A19-B6-CS0; A20-B6-C26; A21-B6-C2; A21-B6-C37; A22-B6-C13; A19-B6-C51; A20-B6-C27; A21-B6-C3; A21-B6-C3S; A22-B6-C14; A19-B6-C52; A20-B6-C28; - A21-B6-C4; A21-B6-C39; A22-B6-C15; A19-B6-C53; A20-B6-C29; A21-B6-CS; A21-B6-C40; A22-B6-C16; A19-B6-CS4; A20-B6-C30; A21-B6-C6; A21-B6-C41; A22-B6-C17; A19-B6-C55; A20-B6-C31; A21-B6-C7; A21-B6-C42; A22-B6-C18; A19-B6-C56; A20-B6-C32; A21-B6-C8; A21-B6-C43; A22-B6-C19; A19-B6-C57; A20-B6-C33; A21-B6-C9; A21-B6-C44; A22-B6-C20; A19-B6-C58; A20-B6-C34; A21-B6-C10; A21-B6-C45; A22-B6-C2I;

. -159- • • to «· . · · · - e, ίβδ « • · ··· · * • · .. · 9: -, -. '· ^; · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · T ·· A22-B6-C22; A22-B6-C57; A23-B6-C33; A24-B6-C9; * A24-B6-C44; A22-B6-C23; A22-B6-C58; A23-B6-C34;  A24-B6-C10; A24-B6-C45; A22-B6-C24; A22-B6-C59; A23-B6-C35; A24-B6-C11; A24-B6-C46; . A22-B6-C25; A23-B6-C1; A23-B6-C36; A24-B6-C12; A24-B6-C47; A22-B6-C26; A23-B6-C2; A23-B6-C37; A24-B6-C13; A24-B6-C48; A22-B6-C27; A23-B6-C3; A23-B6-C38; A24-B6-C14; A24-B6-C49; A22-B0-C28; A23-B6-C4; A23-B6-C39; A24-B6-C15; A24-B6-C50; A22-B6-C29; A23-B6-C5; A23-B6-C40; A24-B6-C16; A24-B0-CS1; A22-B6-C30; A23-B6-C6; A23-B6-C41; A24-B6-C17; A24-B6-C52; A22-B6-C31; A23-B6-C7; A23-B6-C42; A24-B6-C18; A24-B6-C53; A22-B6-C32; A23-B6-C8; A23-B6-C43; A24-B6-C19; A24-B6-CS4; A22-B6-C33; A23-B6-C9; A23-B6-C44; A24-B6-C20; A24-B6-C55; A22-B6-C34; A23-B6-C10; A23-B6-C45; A24-B6-C21; A24-B6-C56; A22-B6-C35; A23-B6-C11; A23-B6-C46; A24-B6-C22; A24-B6-C57; A22-B6-C36; A23-B6-C12; A23-B6-C47; A24-B6-C23; A24-B6-C58; A22-B6-C37; A23-B6-C13; A23-B6-C48; A24-B6-C24; A24-B6-C59; A22-B6-C38; A23-B6-C14; A23-B6-C49; A24-B6-C25; A25-B6-C1; A22-B6-C39; A23-B6-C15; A23-B6-CS0; A24-B6-C20; A25-B6-C2; A22-B6-C40; A23-B6-C16; A23-B6-C51; · A24-B6-C27; A25-B6-C3; A22-B6-C41; A23-B6-C17; A23-B6-C52; A24-B6-C28; A25-B6-C4; A22-B6-C42; A23-B6-C18; A23-B6-C53; A24-B6-C29; ‘ A25-B6-C5; A22-B6-C43; A23-B6-C19; A23-B6-C54; . A24-B6-C30; A25-B6-C6; A22-Bo-C44t A23-B6-C20; A23-B6-C55; A24-B6-C31; A25-B6-C7; A22-B6-C45; A23-B6-C21; A23-B6-C56; A24-B6-C32; A25-B6-C8; A22-B6-C46; A23-B6-C22; A23-B6-C57; A24-B6-C33; A25-B6-C9; A22-B6-C47; A23-B6-C23; A23-B6-C58; A24-B6-C34; A25-B6-C10; A22-B6-C48; A23-B6-C24; A23-B6-C59; A24-B6-C35; A25-B6-C11; A22-B6-C49; A23-B6-C25; A24-B6-C1; A24-B6-C36; A25-B6-C11: A22-B6-C50; A23-B6-C26; A24-B6-C2; A24-B6-C37; A25-B6-C13; A22-B6-C51; A23-B6-C27; . A24-B6-C3; A24-B6-C38; A25-B6-C14; A22-B6-C52; A23-B6-C28; A24-B6-C4; A24-B6-C39; A2S-B6-C15; A22-B6-C53; A23-B6-C29; A24-B6-C5; _ι A24-B6-C40; A25-B6-C17: A22-B6-C54; A23-B6-C30; A24-B6-C6; A24-B6-C41; A25-B6-C17; A22-B6-C55; A23-B6-C31; A24-B6-C7; A24-B6-C42; A25-B6-C1S; A22-B6-C56; A23-B6-C32; A24-B6-C8; A24-B6-C43; A25-B6-C19;

A25-B6-C20;

A25-B6-C21;

A25-B6-C22;

A25-B6-C23;

A25-B6-C24;

A25-B6-C25;

A25-B6-C26;

A25-B6-C27;

A25-B6-C28;

A25-B6-C29;

A25-B6-C30;

A25-B6-C31;

A25-B6-C32;

A25-B6-C33;

A25-B6-C34;

A25-B6-C35;

A25-B6-C36;

A25-B6-C37;

A25-B6-C38;

A25-B6-C39;

A25-B6-C40;

A25-B6-C41;

--- A25-B6-C42;

A25-B6-C43;

A25-B6-C44;

A25-B6-C45;

A25-B6-C46;

A25-B6-C47;

A25-B6-C48;

A25-B6-C49;

A25-B6-C50;

A25-B6-C51;

A25-B6-CS2;

A25-B6-CS3;

A25-B6-C54;

-160- • ‘40 • · · · • · · 9 9 • · • · · · · 9 · ♦ '· ♦ ····. • 9 9 9 · · • 9 4 9 9 · · • «« ····· « • β β 9 · 99 4 '·· · A25-B6-C55; A26-B6-C31; A27-B6-C7; A27-B6-C42; A25-B6-C50; A26-B6-C32; A27-B6-C8; A27-B6-C43; A25-B6-C57; A26-B6-C33; A27-B6-C9; A27-B6-C44; A25-B6-C58; A26-B6-C34; A27-B6-C10; A27-B6-C45; A25-B6-C59; A26-B6-C35; A27-B6-C11; A27-B6-C46; A26-B6-C1; A26-B6-C36; A27-B6-C12; A27-B6-C47; A26-B6-C2; A26-3O-C37; A27-B0-C13; A27-B6-C48; A26-B6-C3; A26-B6-C38; A27-B6-C14; A27-B6-C49; A26-B6-C4; A26-B6-C39; A27-B6-C15; A27-B6-C50; A26-B6-C5; A26-B6-C40; A27-B6-C16; A27-B6-C51; A26-B6-C6; A26-B6-C41; A27-B6-C17; A27-B6-C52; A26-B6-C7; A26-B6-C42; A27-B6-C18; A27-B6-C53; A26-B6-C8; . A26-B6-C43; A27-B6-C19; A27-B6-C54; A26-B6-C9; A26-B6-C44; A27-B6-C20; A27-B6-C55; A26-B6-C10; A26-B6-C45; A27-B6-C21; A27-B6-C56; A26-B6-C11; A26-B6-C46; A27-B6-C22; A27-B6-C57; A26-B6-C12; A26-B6-C47; A27-B6-C23; A27-B6-C58; A26-B6-C13; ₄ A26-B6-C47: A27-B6-C24; A27-B6-C59; A26-B6-C14; A26-B6-C49; A27-B6-C25; A28-B6-C1; A26-B6-C15; A26-B6-C50; A27-B6-C26; A28-B6-C2; A26-B6-C16; A26-B6-C51; A27-B6-C27; A28-B6-C3; A26-B6-C17; A26-B6-C52; A27-B6-C28; A28-B6-C4; A26.B6-C18t A26-B6-C53; A27-B6-C29; A28-B6-C5; A26-B6-C19; A26-B6-C54; A27-B6-C30; A2S-B6-C6; A26-B6-C20; A26-B6-C55; A27-B6-C31; A28-B6-C7; A26-B6-C21; A26-B6-C56; A27-B6-C32; A28-B6-C8; A26-B6-C22; A26-B6-C57; A27-B6-C33; . A28-B6-C9; A26-B6-C23; A26-B6-C58; A27-B6-C34; A28-B6-C10; A26-B6-C24; A26-B6-C59; A27-B6-C35; A28-B6-C11; A26-B6-C25; A27-B6-C1; A27-B6-C36; A28-B6-C12; A26-B6-C26; A27-B6-C2; A27-B6-C37; A28-B6-C13; A26-B6-C27; A27-B6-C3; A27-B6-C38; A28-B6-C14; A26-B6-C28; A27-B6-C4; A27-B6-C39; A2S-B6-C15; A26-B6-C29; A27-B6-C5; A27-B6-C40; A28-B6-C16; A26-B6-C30; A27-B6-C6; A27-B6-C41; A28-B6-C17;

· .161 · * * · · · · · · * ·. * # # # # # # # # # # # # # # # # # # #

· · · · · · · · · · · · · ·

A28-B6-C18; A28-B6-C53; A29-B6-C29; A30-B6-C5; A30-B6-C40; A28-B6-C19; A28-B6-C54; A29-B6-C30; A30-B6-C6; A30-B6-C41; A28-B6-C20; A28-B6-C55; A29-B6-C3I; A30-B6-C7; A30-B6-C42; A28-B6-C21; A28-B6-C56; A29-B6-C32; A30-B6-C8; A30-B6-C43; A28-B6-C22; A28-B6-C57; A29-B6-C33; A30-B6-C9; A30-B6-C44; A28-B6-C23; A28-B6-C58; A29-B6-C33: A3O-B6-C10; A30-B6-C45; A28-B6-C24; A28-B6-C59; A29-B6-C35; A30-B6-C11; A30-B6-C46; A28-B6-C2S; A29-B6-C1; A29-B6-C36; A30-B6-C12; A30-3O-C47; A2S-B6-C26; A29-B6-C2; A29-B6-C37; A30-B6-C13; A30-B6-C48 A28-B6-C27; A29-B6-C3; A29-B6-C38; A30-B6-C14; A30-B0-C49; A28-B6-C28; A29-B6-C4; A29-B6-C39; A30-B6-C15; A30-B6-CS0; A28-B6-C29; A29-B6-CS; A29-B6-C40; A30-B6-C16; A30-B6-C51; A28-B6-C30; A29-B6-C6; A29-B6-C41; A30-B6-C17; A30-B6-C52 A28-B6-C31; A29-B6-C7; A29-B6-C42; A30-B6-C18; A30-B6-C53; A2S-B6-C32; A29-B6-C8; A29-B6-C43; A30-B6-C19; A30-B6-C54; A28-B6-C33; A29-B6-C9; A29-B6-C44; A30-B6-C20; A30-B6-C53; A2S-B6-C34; A29-B6-C11: A29-B6-C45; A30-B6-C21; A30-B6-C50; A28-B6-C35; A29-B6-C11; A29-B6-C46; A30-B6-C22; A30-B6-C57; A28-B6-C36; A29-B6-C12; A29-B6-C47; A30-B6-C23; A30-B6-CS3; A28-B6-C37; A29-B6-C13; A29-CA-C4S; A30-B6-C24; A30-B6-C59; A28-B6-C38; A29-B6-C14; A29-B6-C49; A30-86-C25; A31-B6-C1; A28-B6-C39; A29-B6-C15; A29-B6-C50; A30-B6-C26; A31-B6-C2; A28-B6-C40; A29-B6-C16; A29-B6-C51; A30-B6-C27; A31-B6-C3; A28-B6-C41; A29-B6-C17; A29-B6-C52; A30-B6-C28; A31-B6-C4; ---- A28-B6-C42; A29-B6-C13; A29-B6-C53; A30-B6-C29; A31-B6-C5; A28-B6-C43; A29-B6-C19; A29-B6-C54; A30-B6-C30; A31-B6-C6; A28-B6-C44; A29-B6-C20; A29-B6-C53; A30-B6-C31; A31-B6-C7; A28-B6-C45; A29-B6-C21; A29-B6-C56; A30-B6-C32; A31-B6-C8; A28-B6-C46; A29-B6-C22; A29-B6-C57; A30B6-C33; A31-B6-C9; A28-B6-C47; A29-B6-C23; A29-B6-C58; A30-B6-C34; A31-B6-C10; A28-B6-C48; A29-B6-C24; A29-B6-C59; A30-B6-C35; A31-B6-C11; A28-B6-C49; A29-B6-C25; A30-B6-C1; A30-B6-C36; A31-B6-Cl2; A28-B6-C50; A29-B6-C26; A30-B6-C2; A30-B6-C37; A31-B6-C13; A28-B6-CS2; A29-B6-C27; A30-B6-C3; A30-B6-C38; A31-B6-C14; A28-B6-C52; A29-B6-C2S; A30-B6-C4; A30-B6-C39; A31-B6-C15;

• · <·. ··· ·· 0, «» · ·. · · ".1 ----- -------- ------------ ·· · - · · · - · ♦ · 0 —------ - ♦ '···' 1 χπ. »· '·» ·· 0 9

-102 ”U · ··· * ······ ♦ ·«

A31-B6-C16; A31-B6-C51; A32-B6-C27; A33-B6-C3; A33-B6-C38; A3I-B6-C17; A31-B6-C52 A32-B6-C28; A33-B6-C4; A33-B6-C39; A31-B6-C18; A31-B0-C53; A32-B6-C29; A33-B6-C5; A33-B6-C40; A31-B6-C19; A31-B6-C54; A32-B6-C30; A33-B6-C6; A33-B6-C41; A31-B6-C20; A31-B6-C55; A32-B6-C31; A33-B6-C7; A33-B6-C42; A31-B6-C21; A31-B6-C56; A32-B6-C32; A33-B6-C8; A33-B6-C43; A31-B6-C22; A31-B6-C57; A32-B6-C33; A33-B6-C9; A33-B6-C44; A31-B0-C23; A31-B6-C53; A32-B6-C34; A33-B6-C10; A33-B6-C45; A31-B6-C24; A31-B6-C59; A32-B6-C35; A33-B6-C11; A33-B6-C47: A31-B6-C25; A32-B6-C1; A32-B6-C36; A33-B6-C12; A33-B6-C47; A31-B6-C26; A32-B6-C2; A32-B6-C37; A33-B6-C13; A33-B6-C48; A31-B6-C27; A32-B6-C3; A32-B6-C38; A33-B6-C14; A33-B6-C49; A31-B6-C28; A32-B6-C4; A32-B6-C39; A33-B6-C15; A33-B6-C50; A31-B6-C29; A32-B6-C5; A32-B6-C40; A33-B6-C16; A33-B6-C51; A31-B6-C30; A32-B6-C6; A32-B6-C41; A33-B6-C17; A33-B6-C52; A31-B6-C31; A32-B6-C7; A32-B6-C42; A33-B6-C18; A33-B6-C53; A31-B6-C32; A32-B6-C8; A32-B6-C43; A33-B6-C19; A33-B6-C54; A3I-B6-C33; A32-B6-C9; A32-B6-C44; A33-B6-C20; A33-B5-CSS; A31-B6-C34; A32-B6-C10; A32-B6-C45; . A33-B6-C21; A33-B6-C50; A31-B6-C3S; A32-B6-C11; A32-B6-C46; A33-B6-C22; A33-B6-C57; A31-B6-C36; A32-B6-C12; A32-B0-C47; A33-B6-C23; A33-B6.CSS; A31-B6-C37; A32-B6-C13; A32-B6-C48; A33-B6-C24; A33-B6-C59; A31-B6-C38; A32-B6-C14; --- A32-B6-C49; A33 * Bo * C2a; A34-B6-C1; A31-B6-C39; A32-B6-C15; A32-B6-C50; A33-B6-C26; A34-B6-C2; A31-B6-C40; A32-B6-C16; A32-B6-C51; A33-B6-C27; A34-B6-C3; A31-B6-C41; A32-B6-C17; A32-B6-C52; A33-B6-G28; A34-B6-C4; A31-B6-C42; A32-B6-C1S: A32-B6-C53; A33-B6-C29; A34-B6-C5; A31-B6-C43; A32-B6-C19; A32-B6-C54; A33-B6-C30; A34-B6-C6; A31-B6-C44; A32-B6-C20; A32-B6-C55; A33-B6-C31; A34-B6-C7; A31-B6-C45; A32-B6-C21; A22-B0-C56; A33-B6-C32; A34-B6-C8; A31-B6-C46; A32-B6-C22; A32-B6-C57; A33-B6-C33; A34-B6-C9; A31-B6-C47; A32-B6-C23; A32-B6-C58; A33-B6-C34; A34-B6-C10; A31-B6-C48; A32-B6-C24; A32-B6-C59; A33-B6-C35; A34-B6-C11; A31-B6-C4S; A32-B6-C25; A33-B6-C1; A33-B6-C36; A34-B6-C12; A31-B6-C50; A32-B6-C26; A33-B6-C2; A33-B6-C37; A34-B6-C13;

- · 4 - 4 9 ύ

-163 · '··. ··' 9 · »« ··

A34-B6-C14; A34-B6-C49; A35-B6-C25; A34-B6-C15; A34-B6-C50; A35-B6-C26; A34-B6-C16; A34-B6-C51; A35-B6-C27; A34-B6-C17; A34-B6-C52; A35-B6-C28; A34-B6-C18; A34-B6-C53; A35-B6-C29; A34-B6-C19; A34-B6-C54; A35-B6-C30; A34-B6-C20; A34-B6-C55; A35-B6-C31; A34-B6-C21; A34-B6-C56; A35-B6-C32; A34-B6-C22; A34-B6-C57; A3S-B6-C33; A34-B6-C23; A34-B6-C58; A35-B6-C34; A34-B6-C24; A34-B6-C59; A35-B6-C35; A34-B6-C25; A35-B6-C1; A35-B6-C36; A34-B6-C26; A35-B6-C2; A35-B6-C37; A34-B6-C27; S3S-B6-C3; A35-B6-C38; A34-B6-C28; A35-B6-C4; A35-B6-C39; A34-B6-C29; A35-B6-C5; A35-B6-C40; A34-B6-C30; A3S-B6-C6; , A35-B6-C41; A34-B6-C31; A35-B6-C7; A23-B0-C42; A34-B6-C32; A35-B6-C8; A35-B6-C43; A34-B6-C33; A35-B6-C9; A35-B6-C44; A34-B6-C34; A35-B6-C10; A35-B6-C45; A34-B6-C35; A35-B6-C11; A35-B6-C46; A34-B6-C36; A35-B6-C12; A35-B6-C47; A34-B6-C37; A3S-B6-C13; A35-B6-C48; A34-B6-C38; A35-B6-C14; A35-B6-C49; 3434-B6-C39; A35-B6-C15; A34-B6-C40; A35-B6-C16; A34-B6-C41; A35-B6-C17; A34-B6-C42; A35-B6-C18; A34-B6-C43; A35-B6-C19; A34-B6-C44; A35-B6-C20; A34-B6-C45; A35-B6-C21; A34-B6-C46; A3S-B6-C22; A34-B6-C47; A35-B6-C23; A34-B6-C48; A35-B6-C24;

·>

164

9 · '· 4 · 4 4 98 4 4 .. 4 4 9 <i 4 ' • 99999 • 4 · 4 · 4 4 4 9 • 4 4 4 9 9 9 9 1 99 and 9 9

and the corresponding N-oxides and prodrugs thereof, and pharmaceutically acceptable salts and solvates (such as hydrates) of these compounds and their N-oxides and prodrugs.

Thus, for example, in the above summary, the compound designated as A1-B1-C1 represents a product obtained by combining the group A1 listed in Table 1 and the group B1 listed in Table 2a of the group C1 listed in Table 3, specifically a compound formulas:

Preferred compounds of the present invention are:

3- (1 - {[3-methoxy-4- (3- [2-methylphenyl] -ureido) -phenyl] -acetyl} -1,2,3,4-tetrahydroquinolin-6-yl) -propionic acid 3- (1 - {[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl} -2,3-dihydro-1H-indol-5-yl) -butyric acid 3- ( 1 - {[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl} -1,2,3,4-tetrahydroquinolin-6-yl) butyric acid 3- (1- { [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl} -2,3-dihydro-1H-indol-5-yl) pentanedioic acid,

165

3- (1 - {[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl} -1,2,3,4-tetrahydroquinoline- 6-yl) -pentanedioic acid, 4- [2-carboxy-1- (1 - {[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl} -1,2,3, 4-tetrahydroquinolin-6-yl) ethylcarbamoyl] -butyric acid, N- [2-carboxy-1- (1 - {[3-methoxy-4- (3-o-tolylureido) -phenyl] -acetyl} -1-acetyl) -1, 2,3,4-tetrahydroquinolin-6-yl) ethyl] succinic acid 3- (1 - {[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl} -1,2, 3,4-tetrahydroquinolin-6-yl) -3 - [(5-methyl-isoxazole-3-carbonyl) -amino] -propionic acid 2- (2-chloro-6-methyl-benzoylamino) -3- [1 - (2,6-dichloro-benzoyl) -1,2,3,4-tetrahydroquinolin-6-yl] -propionic acid 2- (2,6-dichloro-benzoylamino) -3- [1- (2,6) -dichlorobenzoyl) -1,2,3,4-tetrahydroquinolin-6-yl) -propionic acid 3- (1 - {[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] - acetyl} -2,3-dihydro-1H-indol-5-yl) -3-phenyl-propionic acid;

3- (1 - {[3-methoxy, -4- (3-o-tolyl-ureido) -phenyl] -acetyl} -2,3-dihydro-1H-indol-5-yl) -pentanoic acid;

and the corresponding N-oxides or prodrugs thereof, or pharmaceutically acceptable salts or solvates thereof (such as hydrates) or N-oxides or prodrugs thereof.

- 166 · i i 4 4 4 β

The compounds of the present invention exhibit useful pharmacological activity and, therefore, can be formulated as pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. The present invention therefore further relates to a further aspect of the compounds as defined above and compositions comprising the compounds of the invention for use in therapy.

The compounds within the scope of the present invention block the interaction of VCAM-1 ligand with its integrin receptor VLA-4 (α4β1), as shown by prior art assays, and by in vivo and in vitro assays which are described below, wherein these assays correlate with pharmacological activity in humans and other animals.

Accordingly, in a further aspect, the present invention relates to compounds and compositions comprising the compounds of the invention for use in treating patients suffering from or susceptible to a disease state which can be alleviated by administration of an α4β1 mediated cell adhesion inhibitor. For example, the compounds of the present invention are useful in the treatment of inflammatory diseases, such as joint inflammation, including arthritis, rheumatoid arthritis and other arthritic conditions such as rheumatoid spodylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis and osteoarthritis. In addition, the compounds of the invention may be used to treat acute synovitis, peripheral vascular events, autoimmune diabetes, autoimmune encephalomyelitis, colitis, atherosclerosis, peripheral vascular disease, cardiovascular disease, (

- 167 multiple sclerosis, asthma, psoriatic restenosis, myocarditis, intestinal inflammation and melanoma cell division in metastases.

According to a particularly preferred embodiment of these therapeutic methods, the present invention relates to the treatment of asthma.

According to another particularly preferred embodiment of these therapeutic methods, the invention relates to the treatment of joint inflammation.

According to another particularly preferred embodiment of these therapeutic methods, the present invention relates to the treatment of inflammatory bowel disease.

In another aspect, the present invention relates to a method of treating a human or animal as a patient suffering from or susceptible to a disease state, which may be alleviated by administering a VCAM-1 ligand interaction inhibitor to its VLA-4 (α4β1) integrin receptor, e.g. as described above, which comprises administering to said patient an effective amount of a compound of the invention or a composition comprising a compound of the invention. By an effective amount is meant an amount of a compound of the present invention that is effective to inhibit the interaction of VCAM-1 ligand at its VLA-4 (α4β1) integrin receptor and thereby elicit the desired therapeutic effect.

As used herein, treatment is intended to include both prophylactic therapy and treatment of the developed condition.

168

44 44 * · »· • • 4 4 4 4 4 4 4 4 4 444 4 4 44444 ·· 4 4

4 4 4 4 4 4

44444 44 4 · 4,444

The present invention also provides pharmaceutical compositions comprising at least one compound of the invention in association with a pharmaceutically acceptable carrier or excipient.

The compounds of the present invention may be administered in any suitable form and in any suitable composition.

In practice, the compounds of the invention may generally be administered parenterally, topically, rectally, orally, or by inhalation, particularly orally.

The compositions of the present invention may be prepared by conventional methods using one or more pharmaceutically acceptable adjuvants or excipients. Adjuvants include, but are not limited to, diluents, sterile aqueous media, and various non-toxic organic solvents. These compositions may be in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, injectable solutions, elixirs or syrups, which may contain one or more agents selected from the group consisting of sweeteners, ______________. flavoring agents, coloring agents and stabilizers to provide pharmaceutically acceptable compositions. The choice of vehicle and the active ingredient content of the vehicle will generally be determined by the solubility and chemical properties of the active agent, the particular mode of administration, and the usual rules of pharmaceutical practice.

Lactose, sodium citrate, calcium carbonate, calcium phosphate and disintegrating agents such as starch, alginic acid and certain complex silicates in combination with lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used as excipients. For the preparation of capsules, it is possible to prepare the capsules

AND"

- 169 9 9 9 9 9 4 9 9 9 9 9 9 9

Preferably, lactose and high molecular weight polyethylene glycols are used. If aqueous suspensions are used, they may contain emulsifying agents or suspending agents. Diluents such as sucrose, ethanol, polyethylene glycol, propylene glycol, glycerol and chloroform or mixtures thereof may also be used.

For parenteral administration, emulsions, suspensions or solutions of the compounds of the present invention in natural oil, such as sesame oil, peanut oil or olive oil, or aqueous-organic solutions such as water and propylene glycol may be used. injectable organic esters such as ethyl oleate as well as sterile aqueous solutions of pharmaceutically acceptable salts. The salt solutions of the compounds of the present invention are particularly suitable for administration by intramuscular or subcutaneous injection. Aqueous solutions may also be used for intravenous administration, which also include solutions of salts in pure distilled water, provided that their pH is appropriately adjusted and that they can be further buffered to give isotonic solutions containing sufficient proportions of glucose, or sodium chloride and further provided that they can be sterilized by heating, irradiation or microfiltration.

For topical administration, gels (aqueous or alcohol based), creams or ointments containing the compounds of the present invention may be used. The compounds of the present invention may also be incorporated in the form of a gel or a matrix based on patches, by controlling

170

• ·· ·· 9 • · ·· · · · • 9 • • »···«) · 9 • · «1 • • · 9 ·· · · · ♦ 9 9

releasing the compound across the transdermal barrier.

When the compounds of the invention are administered by inhalation, they can be dissolved or suspended in a suitable carrier and used as a nebulizer or suspension or aerosol solution, or can be absorbed or adsorbed on a suitable solid carrier and used. in the form of dry powder for inhalers.

Solid formulations for rectal administration include suppositories formulated by conventional methods of the prior art containing at least one compound of the present invention.

The percentage of active ingredient in the composition of the present invention may vary considerably as desired to provide a suitable dosage of the compound of the present invention. Usually, several dosage forms may be administered at approximately the same time intervals. The dosage used may be determined by the attending physician, depending on the therapeutic effect desired, the method of administration and the duration of treatment, as well as the condition of the patient. For adult patients, the dose is generally in the range of about 0.001 to about 50 milligrams / kilogram body weight, preferably about 0.001 milligrams to about 5 milligrams per kilogram body weight for inhalation, in the range of about 0.01 milligrams to about 5 milligrams per kilogram body weight. about 100 milligrams per kilogram body weight, preferably about 0.1 milligrams to about 0.1 milligrams 70 milligrams per kilogram body weight, especially 0.5 milligrams to about 10 milligrams per kilogram body weight per day in the case of oral

171 administration, and in the range of about 0.001 milligrams to about 10 milligrams, ⁴ preferably about 0.01 milligrams to about 1 milligrams per kilogram of body weight per day for intravenous administration. In each individual case, this dose will depend on factors that are critical for each subject being treated, i.e., the patient's age, weight, general health, and other characteristics that may affect the efficacy of the pharmaceutical product.

The compounds of the present invention may be administered as often as necessary to obtain a therapeutic effect. In some patients, the response may occur very quickly to both high and low doses, so that adequate, much weaker acting doses may be selected. In the case of other patients, the use of long-term treatment in an amount ranging from 1 dose to 4 doses per day may be contemplated according to the physiological requirements of each individual patient. In general, the active ingredient may be administered orally one to four times a day. Of course, for some patients, it will be necessary to prescribe a maximum of one or two doses per day.

The compounds of the present invention can be prepared by applying or adapting well known methods known in the art to mean methods which have hitherto been used or described in the literature, such as those described in R.C. Larock, Comprehensive Organic Transformate ions, VCH publishers, 1989.

In carrying out the reactions described herein, it may be necessary to protect reactive functional groups such as

- 172 · · * · 172.. 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, for example hydroxy, amino, imine, thio or carboxy, when their presence in the final product is required to avoid undesired participation in the reactions performed.

In these cases, commonly known and used protecting groups can be used, using conventional methods known in the art, such as T.W. Greene, P.G.M. Wuts, Protective Groups in Organic Chemistry, John Wiley &amp; Sons, 1991.

Compounds of formula I in which R, R, A, L and Z are as defined above and Y is carboxy may be prepared by hydrolyzing esters of a compound of formula I wherein R ¹ , R ² , A ¹ , L ¹ and Z ¹ have the same meaning as previously described and Y represents a -CC 1 R 5 group. (wherein R ^XD represents an alkyl group, an alkenyl group, or an arylalkyl group). The hydrolysis can be carried out in a conventional manner by alkaline hydrolysis using a base such as an alkali metal hydroxide such as lithium hydroxide or an alkali metal carbonate such as potassium carbonate in the presence of a mixture of water and an organic solvent using organic solvents such as dioxane, tetrahydrofuran or methanol, and are operated at a temperature in the range of about ambient temperature to about the reflux temperature of the solvent used. Hydrolysis of the esters can also be accomplished by acid hydrolysis using an inorganic acid such as hydrochloric acid in the presence of a mixture of water and an inert organic solvent such as dioxane or tetrahydrofuran at a temperature ranging from

173 ·

4 about 50 ° C to about 80 ° C.

Another example is the preparation of compounds of formula (I) of the present invention wherein R 1 is a compound of formula (I). R ² and ^ ·, ΐΛ and are as defined above and Y is carboxy, which consists of removing the tertiary butyl group of tert-butyl esters of a compound of formula I in which R, R, A, L and Z ^and Maj I above and Y is -CO ₂ R 6 (where R ³ - 6 is tert-butyl) by acid catalysis using standard reaction conditions generally known and known in the art, e.g. reaction with trifluoroacetic acid at about ambient temperature.

Another example is the preparation of the compounds of formula (I) of the present invention wherein R 1, R ² , A 4 -, ΐΛ and z 7 are as defined above, wherein Y is a carboxy group which is carried out by hydrogenation of the compounds of formula I wherein R, R, A, L and Z are as defined above and Y is -CO ₂ R ¹⁶ (in which R 6 is a -CO ₂ R ¹⁶ group wherein R ¹⁶ is an arylmethyl group such as e.g. benzyl group). The reaction may be carried out in the presence of ammonium formate and a suitable metal catalyst such as palladium supported on an inert support such as carbon, preferably in a solvent such as methanol or ethanol and at about the reflux temperature of the solvent. This reaction may alternatively be carried out in the presence of a suitable metal catalyst, such as platinum or palladium, which is optionally deposited.

• Φ ·

174

on an inert support material such as carbon, preferably in a solvent such as methanol or ethanol. This reaction is most suitable for the preparation of compounds of formula I in which ΐΛ does not contain carbon-carbon multiple bonds.

Using process A to prepare compounds of formula I of the present invention containing an amide linkage, the acid (or acid halide or anhydride) is added to the amine using standard peptide bonding conditions, which will be described further to provide amide bond.

An example of this process A is a process wherein Z is a compound of formula I wherein R,

A ¹ , ΐΛ and Z ¹ are as defined above, and R ¹ represents a group selected from the group consisting of R -Z-, R -L -R -Z-, R ³ -L ³ -Ar ⁴ -L ⁴ -Z ³ - and R ³ -L ³ -Ar - * - L ² -R ⁴ -Z ³ - (in which R ³ , R ⁴ ,

L ² , L ³ . L ³ and Ar ³ have the same meaning as previously defined and Z ³ represents the group C (= O)].

(I) treating the bromo-vang resin (which is

4-bromomethylphenoxylated styrene / divinylbenzene copolymer) _of 1 1 2 1 with an acid of formula (II) in which A, Z, R and L have the same meaning as previously defined and R is a suitable imino protecting group such as 9H-fluorene A -9-ylmethoxycarbonyl group, in the presence of a tertiary amine such as diisopropylethylamine and cesium iodide, in an inert solvent such as dimethylformamide, at a temperature approximately equivalent to room temperature, to obtain resin A:

- 175- • · t · t>!!!!!!!!!!!! · · · ·

(Brom-Vang resin) (Resin A)

means a polymeric core comprising polystyrene crosslinked with 1% to 2% divinylbenzene;

(ii) followed by treatment of resin A with piperidine in an inert solvent such as dimethylformamide at a temperature approximately equal to room temperature to obtain resin B:

- .176

(Resin Β) wherein A ¹ , Z ¹ , R ² , L ¹ and as above.

(iii) Reaction of resin B with a compound of formula III wherein R ¹⁸ is R ³ -, R ³ -L ² -R ⁴ -, R ³ -R 2 -Ar-LL ⁴ or R ³ -L ³ -Ar ¹ -L ² -R ⁴ - (wherein R ³ , R ⁴ , L ² , L ³ , Ar ¹ and L ⁴ have the same meaning as previously defined) and 'X ¹ represents hydroxy or halogen, preferably a chlorine atom to obtain a resin C in which R ² , R ¹⁸ , A ¹ , Z ¹ , L ¹ and as mentioned above have the same meaning [if X ¹ is a hydroxy group, this reaction can be carried out using standard peptide addition methods, for example by addition in the presence of O- (7-azabenzotriazole-

• ·····················

177

-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate and triethylamine (or diisopropylethylamine) in tetrahydrofuran (or dimethylformamide) at room temperature. When it is a halogen atom, the acylation reaction is carried out using a base such as pyridine, preferably in a solvent such as tetrahydrofuran and at a temperature corresponding to approximately room temperature]:

(iv) followed by treatment of resin C with trifluoroacetic acid in an inert solvent such as dichloromethane at a temperature corresponding to about room temperature.

A further example of process A is a process wherein the compounds of formula I wherein R 1, A ³ , Y and Z ³ have the same meaning as previously defined and L ¹ contains the group -N (R ⁸ ) - C (= O) -R ⁹ (wherein R ⁸

- 178 ·· ':

·· · «·: ::. And have the same meaning as defined above) prepared by reaction of the corresponding compounds of formula I in which R ^J

R, A ¹ , Y and Z ¹ have the same meaning as previously

R R is as defined above and L comprises an -NH (R °) group (in which R has the same meaning as previously defined) with acids (or acid chlorides) of the general formula:

R ⁹ -C (= O) -X ¹ wherein R ⁹ and have the same meaning as previously defined using conventional coupling reaction conditions, for example the conditions set forth above.

R ²

Esters of compounds of formula (I) in which A ¹ and Z ¹ have the same meaning as previously defined, Y represents a> 16 -CO 2 R 16 group (wherein R ^xo has the same meaning as above) and L ³ contains the group -N (R 2). -C (= O) -R (wherein R ⁸ and R ⁹ have the same meaning as previously defined) may be prepared in a similar manner from the corresponding esters of formula I in which L ^x contains the + NHR group (in which R ⁸ has the same meaning as defined above), by reaction with a compound of the general formula:

R ⁹ -C (= O) -X ¹¹ t

wherein R ⁹ and X ¹ have the same meaning as previously defined. · '* 2

Esters of the compound of formula I in which,

A ¹ , L ¹ , and as defined above, rV is a group of 3 3 3 2 43 selected from the group consisting of R -Z-, R -L -R -Z-, R--ÁA-Ar ^ -L ^ -Z ^3- and R ³ -L ³ -Ar 4 -L ² -R 4 -Z ³ - [in which R ³ , R 4, L ² , L ³ , L ³ and Ar · ¹ have the same meaning as previously defined

• • • • • • • • • • • • • • • • • 4 4

179 • ··· · · · 4444 · · 4

4 4 4 4 4 5

And Z ³ is C (= O)] and Y is -CO ₂ R ¹⁶ (in which R ¹ is as defined above) may be prepared by reacting a compound of formula III, wherein R ¹⁸ is R ³ -, R ³ -L ² -R ⁴ -, R ³ -L ³ -Ar ¹ -L ⁴ - or R ³ -L ³ -Ar ¹ -L ² -R ⁴ - (in which R ³ , R ⁴ , L ² , L ³ , Ar ¹ and L ⁴ have the same meanings as above) and X ¹ represents a hydroxy group, a halogen atom, preferably a chlorine atom, with an amine of formula IV:

_CO2 ^R16 (IV) wherein R ^2, A ^1, L ^1, Z ¹ and R ¹⁶ have the same meanings as defined above, using standard conditions of conventional addition reaction, for example, the abovementioned conditions.

Esters of the compounds of formula I in which R,

A ¹ , L ¹ and Z ¹ have the same meanings given above, R ¹ represents' ^Ί - ^- 77 7 3 and ^- * --- ^{: - a} group selected from the group consisting of R -Z-,

R ³ -L ² -R ⁴ -Z ³ -, R ³ -L ³ -Ar ¹ -L ⁴ -Z ³ - and R ³ -L ³ -Ar ¹ -L ² -R ⁴ -Z ³ - (in which R ³ , R ⁴ , L ² , L ³ , L ³ and Ar ¹ have the same meaning as previously defined and Y ³ is SO ₂ ) and Y is -CO ₂ R ¹⁶ (in which R ¹⁶ has the same meaning as as described above) may be prepared by sulfonylation of a compound of formula IV wherein R ² , A ¹ , L ¹ , Z ¹ and R ¹ are as defined above, using a sulfonyl chloride of formula V:

r ¹⁸ -so ₂ ci (A)

180

• ·· «9 • ·· • »4 «4 • • · 4 4 4 4444 • 4 4 • ¹ 4 • 4 • 4 4 • 4 44 • 4 • ··

in which it has the same meaning as previously defined.

This reaction is preferably carried out using a base such as a tertiary amine such as triethylamine, preferably in a solvent such as tetrahydrofuran at a temperature ranging from about 0 ° C to room temperature.

Esters of formula I in which R, R, A and Z have the same meaning as previously defined, Y is -CO ₉ R ¹⁵ (in which R ¹⁶ is as defined above) and L ¹ contains the group -N (R °) -SO ₂ -R (in which R ® and R ⁹ have the same meaning as previously defined) may be prepared in a similar manner to the corresponding esters of formula (I) in which iO 0 contains the group -NHR ° (in which R 0 has the same meaning as defined above) by reaction with sulfonyl chlorides of the general formula:

R ⁹ -SO ₂ Cl wherein R ⁹ has the same meaning as defined above.

~ ~ --— About ^- · ..........

Esters of the compounds of formula I in which R,

A - * -, iA and tZ have the same meaning as previously defined, R 1 represents the group 1 - 1A - Ar ¹ - 1A - Z ³ - (in which R ³ , L ³ , L ⁴ and Ar ¹ have α

as defined above, Z ' ³ is a group

NHC (= O) and Y is -CO ₂ R ¹⁶ (wherein R ¹⁶ has the same meaning as previously defined)), can be prepared by "211 reaction of compounds of formula IV wherein R, A, L,

Z 1 and R ⁵ have the same meaning as defined above, with the isocyanate of formula VI:

R ³ -L ³ -Ar ¹ -L ⁴ -NCO (VI) ♦ · • ·

181 •?

• · i ··· · · · · · ·•••••• i · · · ·. In which R ³ , L ³ , L ⁴ and Ar ^{1 have the} same meaning as previously defined. This reaction is preferably carried out with a base such as a tertiary amine such as triethylamine, preferably in a solvent such as dichloromethane and at a temperature approximately equal to room temperature.

Esters of the compounds of formula I in which R,

A · * ^- , L ¹ and τλ have the same meaning as above, R ¹ represents a group R ³ -Z ³ - [in which R ³ has the same meaning as defined above and Z ³ represents a group NHC (= O)] prepared in a similar manner by reaction of a compound of formula IV wherein R ² , A ¹ , L ¹ , Z ¹ and R ¹⁶ have the same meaning as previously defined with an isocyanate of formula

R ³ -NCO 'wherein R ³ has the same meaning as previously defined.

’2

Esters of the compounds of formula I in which R,

-A ^ y-LZ * - pi 7 - * - s maj stej Nu uvedenv above defined, represents a group R ³ -Z ³ - (in which R ³ has the same meaning as previously defined [except aryl and heteroaryl] and Z 0 represents a direct bond), R -L -R -Z-,

R ³ -l ³ -Ar ¹ -L ⁴ -Z ³ - or R ³ -L ³ -Ar ¹ -L ² -R ⁴ -Z ³ - (in which R ³ ,

L ² , L ³ , L ^4, and Ar 2 · have the same meaning as above, and Z ³ is a direct bond) and Y is -CC 2 R 4 (in which it has the same meaning as defined above) can be prepared alkylation of a compound of formula IV wherein R ² , A ¹ , L ¹ , Z ¹ and R ¹ are as defined above using a compound of formula VII:

- 182 • · r ³ -x ² (VII) in which:

R ³ has the same meaning as described immediately above, and

X ² is halogen, preferably bromine. For example, the alkylation may be carried out in the presence of a base such as an alkali metal hydride such as sodium hydride in dimethylformamide or dimethyl sulfoxide at a temperature ranging from about 0 ° C to about 100 ° C.

i 2

Esters of compounds of formula I wherein R, R,

A ¹ and Z ¹ have the same meaning as defined above,

Y is -CO ₂ R ¹⁶ (wherein R ¹⁶ has the same meaning as -JQ as defined above) and L contains an -NHR group (wherein R ⁸ is alkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl ) may be prepared in a similar manner by alkylation of the corresponding derivative of the general formula

formula (I) - in which L 1 contains an -NH ₂ group with a suitable alkyl halide (or arylalkyl halide, cycloalkylalkyl halide, heteroarylalkyl halide or heterocycloalkylakyl halide).

¹ 9 1

Esters of the compounds of formula I wherein R, A,

L ¹ and Z ¹ have the same meaning as previously defined, R ¹ represents a group from the group R -Z - [in which R has the same meaning as defined above and Z represents the group OC (= O)] can be prepared by reacting a compound of general formula of formula IV wherein R ² , A ¹ , L ¹ , Z ¹ and R ¹ have the same meaning as previously defined with a compound of formula VIII:

183

Φ ·· ♦ · · • Φ'Φ • · Φ · Φ • ΦφΦ «· · · · · · Φ Φ Φ Φ • · · Q Φ Φ Φ ·· * · Φ ·· Φ

r3-O-C (= 0) -X ³ (VII) in which:

R ³ has the same meaning as previously defined and

X ³ is a halogen atom, preferably a chlorine atom, in the presence of a suitable basic agent such as triethylamine or pyridine, and at a temperature ranging from about 0 ° C to about room temperature.

2

Esters of the compounds of formula I wherein R, R, A ¹ and Z ¹ have the same meaning as previously defined,

Y is -CO ₂ R ¹⁶ (wherein R ¹⁶ has the same meaning as previously defined) and L ¹ contains the group -N (R ⁸ ) -C (= O) -OR ^{9 * *} (in which R ⁸ and R ^{8 9} have the same meaning as defined above), can be prepared in a similar manner from the corresponding derivatives of formula I in which L contains the group -NHR ⁸ (in which R ⁸ has the same meaning as defined above) by reaction with compounds of the formula:

R ⁹ OC (= O) -X ^{3 *} wherein R ⁹ and X ³ have the same meaning as previously defined.

Esters of compounds of formula I wherein R, R,

A- * · and t0 have the same meaning as defined above,

Y is -CO ₂ R ¹⁶ (wherein R ¹⁶ has the same meaning as previously defined) and iA is a group

- 184 _-CH-O - (or _-CH-CH2 -)

IA NH ₂ NH ₂ may be prepared by hydrogenation of the corresponding derivatives of compounds of formula I in which ΐΛ is -CH-CH ₂ -

AND

N (CH ₂ Ph) ₂ —CH — CH—

I. (or CH ₃ '/ ")" CH "CH,

I I

Ph ph

The reaction may be carried out in the presence of formic acid and a suitable metal catalyst, such as palladium on an inert support material such as carbon, at a temperature of about 60 DEG C. This reaction may conveniently be carried out in the presence of a suitable metal catalyst. , such as platinum or palladium, optionally deposited on an inert support material such as carbon, preferably in a solvent such as methanol or ethanol.

2

Esters of the compounds of formula I wherein R, R, A ¹ and Z ¹ have the same meaning as previously defined,

Y is -CO ₂ R ¹⁶ (wherein R ¹⁶ has the same meaning as previously defined) and ΐΛ is ¢. ·· ·· · ·· »·· ♦ φ φ φ ·, φ φφφ

9 9 '· · Φ · .- · ^τ ·' ·

- 1 R 5 - ^R * ··· · s> φφφφ · φ> ♦

J- θ '*' 9, 9 · φφ · Φ * ···. »« · »’ · —CH — CH—. )

ŇHj.

—GH — CH ₂ - (or "v" in ₂ ) can also be obtained from the corresponding racemic mixture by standard recrystallization of a suitable salt (such as tartrate salt recrystallization) or by applying standard enzymatic cleavage procedures (e.g., using procedures described in Soloshonok) , V. A et al., Tetrahedron Asymmetry 6 (1995) 7, 1601-1610).

12 _f Esters of the compounds of formula I wherein R, R, A ¹ and Za have the same meanings as defined above,

Y is -CO ₂ R ¹⁶ (in which R ¹ is as defined above) and L ¹ is -CH ₂ -CH ₂

N (CH ₂ Ph) ₂ ^·:, • -CH-CH;

(or group

CH,

CH

AND

Ph

CH,

Ph can be prepared by reacting an ester of a compound of formula I wherein R ¹ , R ² , A ¹ and z A have the same meaning as previously defined, Y is -CO ₂ R - * - 6 (wherein R 6 is the same as as defined above) and if is

186

-CH = CH-, with an alkali metal hydride such as sodium hydride in an inert solvent such as tetrahydrofuran and at a temperature approximately equal to room temperature, followed by reaction with the anion derived from the dibenzylamine treatment or (S) - Of N-benzyl-α-methylbenzylamine with butyllithium at about -78 ° C.

2

Esters of the compounds of formula (I) in which R, R, A, *, and ΐΛ have the same meaning as previously defined,

Y is -CO ₂ R ¹⁶ (wherein R ¹⁶ has the same meaning as previously defined) and ΐΛ comprises an alkenylene group, an alkynylene group or a cycloalkenylene group in which an aliphatic carbon-carbon multiple bond is attached directly to the phenyl moiety in the general formula I, may be prepared by coupling compounds of formula IX:

in which R ¹ ,. R ² , A ¹ and Z ^{1 have the} same meaning as above and X ⁴ represents a halogen atom, preferably a bromine or iodine atom, with a compound of formula X:

r ¹⁹ -co ₂ r ¹⁶ (X) in which:

r 16 has the same meaning as defined above and

187 ^R19 is alkenyl, alkynyl or cycloalkenyl.

When X ⁴ is bromine or iodine, the reaction may be carried out in the conventional manner in the presence of palladium acetate, a triarylphosphine compound such as tri-o-tolylphosphine, and a tertiary amine such as tributylamine at a temperature in the range up to about Mp 110 ° C. This reaction is particularly suitable for the preparation of esters of compounds of formula I wherein L ¹ is a vinylene group. When X ⁴ is a chlorine atom, this reaction may be carried out in the usual manner in the presence of sodium iodide, nickel bromide, bis (dibenzylideneacetone) palladium, triarylphosphine such as tri-o-tolylphosphine and a tertiary amine such as tributylamine temperature in the range up to about 110 ° C.

According to another aspect of the present invention, the compounds of the present invention may be prepared by mutual conversion from other compounds of the present invention.

For example, the compounds of formula I of the invention wherein R ¹ , R ² , A ¹ , L ¹ and Z ^{1 have the} same meaning as previously defined and Y is -C (= O) -NHOH is as defined above. can be prepared by reacting a compound of formula (I) wherein R ¹ , R ² , A ¹ , L ¹ and Z ^{1 have the} same meaning as previously defined and Y represents a carboxy group with hydroxylamine using a standard well known peptide coupling method such as for example, treatment with carbodiimide, for example, dicyclohexylcarbodiimide may be used in the presence of triethylamine in an inert solvent such as dichloromethane or tetrahydrofuran at a temperature approximately equal to room temperature. This copulation

188

the reaction can also be carried out using

1-hydroxybenzotriazole and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide in dichloromethane at room temperature. This preparation can also be carried out using

O-protected hydroxylamine; or

O- (tetrahydropyranyl) hydroxylamine followed by acid treatment.

As another example of a process for the conversion of compounds of the present invention, a compound of formula (I) containing a sulfoxide linkage can be prepared from the corresponding compounds containing an -S-linkage. For example, the oxidation may be carried out in a conventional manner by reaction with a peracid such as 3-chloroperbenzoic acid, preferably in an inert solvent such as dichloromethane, preferably at or near room temperature, or it may be using an alternative method using potassium peroxymonosulphate and carrying out the process in a medium such as an aqueous solution of methanol buffered to about pH 5 at a temperature in the range of about 0 ° C to room temperature. This latter method is advantageous for the preparation of compounds containing labile acidic groups.

A further example of a process for the mutual conversion of compounds of the present invention is the process wherein compounds of Formula I of the present invention which contain a sulfone linkage can be prepared by oxidation of the corresponding compounds containing a -S- or sulfoxide linkage. For example, the oxidation can be carried out in a conventional manner using a reaction with a peracid such as an acid

189

• · · · · · · · · · · · · · · · · · · · · · ·

3-chloroperbenzoic acid, preferably in an inert solvent such as dichloromethane, preferably at or near room temperature.

Another example of a process for converting the compounds of the present invention is the process wherein the compounds of Formula I of the present invention are:

R, A, Z, and Y have the same meaning as previously defined and L ¹ is an optionally substituted alkylene group, prepared by hydrogenation of the corresponding compounds of formula I wherein ΐΛ represents the corresponding optionally substituted alkenylene group. The hydrogenation may be carried out using hydrogen (optionally under hydrogen pressure) in the presence of a suitable metal catalyst such as platinum or palladium, optionally supported on an inert support material such as carbon, preferably in a solvent such as methanol or ethanol and at a temperature approximately equal to room temperature.

As another example of a process for the conversion of compounds of the present invention, one may include a process wherein the compounds of Formula I of the present invention wherein R ¹ ,

111 ’

R, A ^x , L / and Z ^x have the same meaning as previously defined, L is an alkylene group substituted by -CONY Y and Y is carboxy, to prepare a reaction of compounds of formula I wherein R, R, A, L, and Z have as defined above, ΐΛ represents an alkylene group substituted with -CO ₂ H and Y represents a carboxy group, with an anhydride such as trifluoroacetic anhydride in an inert solvent such as tetrahydrofuran, followed by treatment with an amine

- 190

ΗΝγ ¹ γ2_

Another example of a process for converting the compounds of the present invention is the process of the present invention wherein the compounds of Formula I of the present invention are those wherein R 2 ₍ a ¹ , R ² and Y have the same meaning as previously defined and Z ¹ is C) (= O), prepared by oxidation of compounds of formula I wherein R ¹ , R ² , A ¹ , L ¹ and Y have the same meaning as previously defined and z 3 represents a CH ₂ group. with potassium permanganate.

As another example of a process of interconversion compounds of the invention include a process in which the compounds of formula I of the invention in which R, R _t and ^1, La and Y are as stej Nu importance j as defined above, and Z ¹ is CH (OH), prepared by reduction of compounds of formula I wherein R 1, R ² , A 1, IA and Y have the same meaning as previously defined and Z 1 is C (= O). For example, this reduction can be carried out in a conventional manner by reaction with sodium borohydride in an aqueous ethanol solution at a temperature corresponding to approximately room temperature.

A further example of a process for the mutual conversion of compounds of the present invention is the process wherein compounds of Formula I of the present invention containing a heterocyclic group in which the heteroatom is a nitrogen atom can be prepared by oxidation to their corresponding N-oxides. Such oxidation may be conveniently carried out by reaction with a mixture comprising hydrogen peroxide and an organic acid such as acetic acid, preferably at or above room temperature, e.g.

191 at a temperature in the range of about 60 to t

Deň: 32 ° C. Alternatively, the oxidation may be carried out by reaction with a peracid such as peracetic acid or m-chloroperbenzoic acid in an inert solvent such as chloroform or dichloromethane at a temperature of about room temperature to reflux, preferably execution at elevated temperature. Alternatively, the oxidation may be carried out by treatment with hydrogen peroxide in the presence of sodium tungstate at a temperature ranging from room temperature to about 60 ° C.

In the case of the compounds according to the invention, it is advantageous to have asymmetric centers. These asymmetric centers may independently be either the R-configuration or the S-configuration. It will be apparent to those skilled in the art that certain compounds of the present invention may also exhibit geometric isomerism. In this connection, it is to be understood that the present invention includes all individual geometric isomers and stereoisomers and mixtures thereof according to the present invention of formula I, including racemic mixtures. These isomers may be separated from their mixtures using conventional methods for similar purposes or modified processes, for example, by chromatographic methods and recrystallization processes, or may be prepared separately from suitable isomers of their intermediates.

In another aspect, the acid addition salts of the compounds of the invention may be prepared by reacting the free bases with a suitable acid using

192

E ¹ ··· ···· · · · · · · · · • · metod.z well known in the art or modified methods. For example, the acid addition salts of the compounds of the invention may be prepared either by dissolving the free base in water or an aqueous alcoholic solution or other suitable solvents containing a suitable acid and separating the salt thus obtained by evaporating the solution, or using the free base reactions. and acids in an organic solvent, in which case the salt is separated directly or can be obtained by concentrating the solution.

The acid addition salts of the compounds of the present invention may be regenerated from the salts by conventional methods known in the art or by modified methods. For example, the parent compounds of the present invention can be regenerated from their acid addition salts by treatment with an alkaline reagent such as an aqueous sodium bicarbonate solution or an aqueous ammonia solution.

The compounds of the present invention can be regenerated from their base addition salts using conventional methods, or prior art methods. For example, the parent compounds of the invention can be regenerated from their base addition salts by treatment with an acid such as hydrochloric acid.

The compounds of the present invention can be prepared or obtained in the conventional manner in the form of solvates (such as hydrates) during the process of the invention. Hydrates of the compounds of the present invention can be prepared in a conventional manner by recrystallization from a mixture of water

-. 193

• ·· • It does it to · . it it • it ·· • · · • ··· • it • this ·· to- · · • · • · ···· it • • to · • · • · '·

and an organic solvent, the organic solvent being dioxane, tetrahydrofuran or methanol.

In another aspect, the base addition salts of the compounds of the present invention can be prepared by reacting the free acid with a suitable base, using any of the known methods or a modified method. For example, the base addition salts of the compounds of the present invention are prepared either by dissolving the free acid in water or an aqueous alcoholic solution or in another suitable solvent containing the appropriate base, then separating the salt by evaporating the solution, or by reacting the free acid. and a base in an organic solvent, in which case the salt is separated directly or can be obtained by concentrating the solution.

The starting materials and intermediates can be prepared by applying conventional methods known in the art or modified by methods. such as, for example, the methods described in the Reference Examples or chemically similar methods.

'-i o

Compounds of formula (III) in which R is R ³ -L ³ -Ar ⁴ -L ⁴ - [(wherein R ³ , R ⁴ , L ² , L ³ , L ⁴ and Ar ¹ have the same meaning as previously defined) supra) can be prepared by using or modifying the methods described in International Patent Application Publication No. WO 96/22966.

Compounds of formula III wherein R 0 is R ³ -L ³ -Ar ¹ -L ⁴ - [(wherein R ³ and L ⁴ have the same meaning as-1 as defined above, L ° is NH, Ar ³ · means

194 group

(wherein R is as defined above)] and χΐ is a hydroxy group, may be prepared by reacting a compound of Formula 1:

HX

H ₂ N

4-l — co 'r (1) in which:

R and L ⁴ have the same meaning as previously defined, R-L 6 is a lower alkyl group and X is O, with isothiocyanates of the general formula:

___'______ R ³ -N = C = O __'___.

(wherein R ³ has the same meaning as previously defined) in ethanol and at room temperature, followed by reaction with a carbodiimide such as dicyclohexylcarbodiimide or diisopropylcarbodiimide in ethanol at a temperature ranging from about room temperature to about room temperature. reflux, followed by hydrolysis carried out under standard conditions, for example those mentioned above.

η o

The acids of formula III where R ^1-0 is

195

• 44 ·· 4 4 .4 4 4 4. 4 4 4 4 4 4 4 4 .4: · · • 4 4 4 4 4 4 4 4 4 4 4 4 44 44 44 4 4 4 4

R 1 -L 1 -Ar 1 -L ⁴ - [(wherein R ³ and L ⁴ have the same meaning as previously defined, Ar ¹ represents a group

R (wherein R is as defined above), L is NH and X ¹ is hydroxy] can be prepared in a similar manner from compounds of formula (1) wherein R, L ⁴ and R ¹⁶ have the same meaning as as defined above and X is NH.

1R

Acid chlorides of formula II where R ^xo is the same as defined above and X ¹ is a chlorine atom may be prepared from the corresponding acids of formula II in which ^R18 has the same meaning as defined above and X ¹ is hydroxy using conventional standard methods known in the art and used to convert acids to acid chlorides, for example, reactions with oxalyl chloride may be used.

". - __. __ _; Compounds of formula (IV) in which R and R have the same meaning as previously defined, Z ¹ is CH ₂ , L ¹ has the same meaning as previously defined (except when: L ¹ contains a non-aromatic carbon-carbon multiple bond) and A ¹ represents an ethylene group, may be prepared by hydrogenation of the corresponding quinoline analogous compounds of formula (2):

(2)

196 • ············

4 9 9

In which R @ 1 and R @ ³³ have the same meaning as defined above and L @ ³ has the same meaning as defined immediately above, in the presence of a suitable metal catalyst. This reduction can be conveniently carried out at 50 bar hydrogen pressure. in the presence of 5% rhodium in a carbon powder catalyst in a hydrochloric acid medium and at a temperature approximately equal to room temperature.

* 7 -i fZ

Compounds of formula (2) wherein R 1 and R 0 have the same meaning as previously defined and L ³ represents an alkylene group may be prepared by an electrochemical addition reaction using a compound of formula (3):

(3) ^ vekíerémR mástejnýyýznam shora_______ as defined and X ⁵ is iodo, or preferably bromo, in the presence of an ester alkenoic acid of the formula X wherein R ³³ has the same meaning as defined above and R is an alkenyl group. The reaction may be carried out in the usual manner in the presence of a nickel salt catalyst such as nickel bromide trihydrate, tetrabutylammonium bromide, tetrabutylammonium iodide and 1,2-dibromoethane, in an inert solvent or in a mixture of inert solvents such as dimethylformamide and pyridine, and at a temperature. about 60 ° C. This reaction is particularly suitable for the preparation of compounds of formula I wherein L ³ is an ethylene group.

197 · 4 · 4 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· · 4 · ··

1 Α

Compounds of formula 2 wherein R 1 and R ¹ have the same meaning as previously defined and ΐΛ is a

alkylene substituted -CH ₂ 0R ^J (such as -CH ₂ OCH ₃₎ may be prepared from compounds of formula 2 wherein R ² and R have the same meanings as defined above, and L ^{* 1} group znamená.alkenylenovou wherein the carbon-carbon double bond is substituted with a methyl group, using the following standard reaction method:

(i) carrying out allylic bromination using N-bromosuccinimide, (ii) replacing the allylic bromo with OR @ ^-3 reacting an alkali metal salt of the formula

R @ ³ O @ ⁺ M @ ⁺ (such as sodium methoxide);

1

Compounds of formula (2) in which R and R have the same meaning as previously defined and ΐΛ represents an alkenylene group, an alkynylene group or a cycloalkenylene group in which a carbon carbon multiple bond is attached directly to the phenyl moiety of the formula

I, may be prepared by reacting a compound of formula (3) wherein R ² is as defined above and X ³ is iodine, or preferably bromine, with a compound of formula X wherein R ¹⁶ and R ¹⁹ have the same as defined above using standard Heck addition reaction conditions, for example, in the presence of palladium acetate, triphenylphosphine and tributylamine at a temperature of up to about 120 ° C.

- 198 -:

• · · · · · · · · · · · · I · · a a a a a a a 0 0,,,,, 0 0,

R ² and R ¹⁶ τ 1 · '.

L means optionally

Compounds of formula (2) in which they have the same meaning as previously defined and an optionally substituted arylene group or a substituted heteroaryldiyl group may be:. .

prepared by reacting a compound of formula (3) wherein R ² has the same meaning as previously defined and X ³ is iodine or bromine with a compound of formula (4):

Br-L ¹ -CO ₂ R ¹⁶ (4), in which it has the same meaning as previously defined and 1A represents an optionally substituted arylene group or an optionally substituted heteroaryldiyl group. The '*''' · '· ^ν «ί' in the presence of a complex metal catalyst such _as; C · -.

for example tetrakis (triphenylphosphine) palladium, and using standard reaction conditions such as those disclosed in Trecourt et al. Tetrahedron, (1995), 43, 11743-11750. .,. 'i ... ··' ₂ ⁽ⁱ

Compounds of formula IV or 2, wherein R and R ³ have the same meanings as defined above, and "LA" Tc group Y is -CH ₂ -CH-. . Nh ₂ can be prepared by standard methods used for the preparation of α-amino acids, such as those described in Organic Syntheses Based On Name Reactions and Unnamed Reactions by A. Hassner and C. Stumer, Pergamon, pp. 275-374.

- 199

16

Compounds of general formula (2) in which R and R have the same meaning as defined above and L ¹ represents a group -CH ₂ -CH ¹ ;

^NH 2 can be prepared by reacting compounds of formula (5):

wherein R ² has the same meaning as previously defined and X ³ represents a bromine or chlorine atom, with the anion derived from the reaction of (2R) - (-) - 2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine with butyllithium, using the method described by DL Boger

-a-Bt. ~ 3-ohannes-, ~ J Org. Chem. [JOCEAH], 1990, 55, used to prepare compounds of Formula 31 on page 6010.

16 1

Compounds of formula (IV) in which R, R, A and Z ¹ have the same meaning as previously defined and L ¹ represents a group -CH ₂ -CH-,

L nh ₂ . can be prepared in a similar manner from compounds of formula (6);

200

1A 1 in which R, A ^x , X 0 and 7 J have the same meaning as previously defined.

1

Compounds of formula (6) wherein R, and Zr one _of and X ° the same meaning as defined above and Z is CH ₂ may be prepared by application or adaptation of the methodological procedures described in U.S. Patent no. 4,156,734, for example, Example 23A describes the preparation of an N-protected dihydroindole,

1-benzoyl-5-chloromethyl-2,3-dihydro-1H-indole from 1-benzoyl-2,3-dihydro-1H-indole (see Beilstein, 20, 257).

Compounds of formula IV in which R, R ^XD and ΐΛ have the same meaning as previously defined, 7p represents a CH ₂ group, A 4 represents a straight chain alkylene group having 1 to 3 carbon atoms and a contains an alkenylene group, an alkynylene group or a cycloalkenylene group in which an aliphatic carbon-carbon multiple bond is attached directly to the phenyl moiety of formula IV may be prepared by addition of a compound of formula (7):

201 »Φ Φ φ φ in which:

R is as defined above, means a straight chain alkylene group having 1 to 3 carbon atoms,

X 'represents a halogen atom, preferably a bromine or iodine atom, and

Z ³ .znamená _CH2, a compound of formula X, wherein R ⁵ has the same meaning as defined above, and R ⁹ is alkenyl, alkynyl or cycloalkenyl. The cross-coupling reaction may conveniently be carried out in the presence of palladium acetate and tris (o-tolyl) phosphine using standard addition conditions such as those set forth above. In this reaction, a suitable NH group protecting group is, for example, a tertiary butyloxycarbonyl group;

1

Compounds of formula (IV) in which R, R and 1A have the same meaning as defined above, will record CH ₂ , A 1 is a straight chain alkylene group having 1 to 3 carbon atoms and 1A contains an alkylene group or a cycloalkylene group, may be prepared by hydrogenation of the corresponding compounds of formula (IV) in which 1A contains an alkenylene group, an alkynylene group or a cycloalkenylene group using standard hydrogenation procedures such as those described above.

O

Compounds of formula (7) in which R represents a hydrogen atom, A ^ represents an ethylene group, Z ^ represents a CH ₂ group and X ⁵ represents an iodine atom attached at the 6-position of the tetrahydroquinoline ring can be prepared by iodination

1,2,3,4-tetrahydroquinoline with iodine chloride in acid

• * · ·

202 acetic at about room temperature.

2,3-Dihydro-4 (1H) -quinolones of general formula (7) in which R represents a hydrogen atom, A represents an ethylene group, Z ¹ represents a C (= O) group and X ° represents a halogen atom attached at the 6-position of the tetrahydroquinoline The ring may be prepared by using or adapting the acid catalyzed rearrangement of Fries-type 1-arylazetidin-2-ones described by S Kano et al., J. Chem. Soc.,

Perkin Trans. 1098, 10, pp. 2105-2111.

A 1

Compounds of formula (IV) in which R, R- ^{1, O} , LU and A 1 · have the same meaning as previously defined and will record a CH ₂ group, wherein 3 is a group -CH-CH ₂ -

CH ₂ CO ₂ Me can be prepared by reacting an ester of a compound of formula 12 L

I, in which Rf. R and A are as defined above, Y is -CO ₂ R (in which R ° - is as defined above), is CH ₂ and iA is -CH = CH-, with dimethyl imalonate in the presence of an alkali metal alkoxide, such as sodium methoxide, in methanol and at reflux temperature.

* 7 1 A 1

Compounds of formula IV in which R, R ^σ and A have the same meanings as defined above, and Z5 represents. _v . _vv 9 is a CH ₂ group, wherein -L -Y represents θ

203 can be prepared by addition of compounds of formula (8) wherein R and A have the same meaning as previously defined and are halogen, preferably bromine or iodine, with 5,6-dihydropyran-2-one in the presence of tetrakis (triphenylphosphine) palladium and triethylamine in an inert solvent such as dimethylformamide at a temperature of about 95 ° C and in a sealed container.

Compounds of formula (IV) wherein R, R ^x , L and A ¹ have the same meaning as previously defined and Z 2 is CH ₂ , wherein ΐΛ comprises the group -N (R ⁸ ) -C (= O) -R ⁹ (wherein R ⁸ and R ⁹ have the same meaning as previously defined), can be prepared from the corresponding compounds of formula IV in which ΐΛ contains the group -NHR ⁸ (in which R ⁸ has the same meaning as defined above) by reaction with a compound of the general formula:

R ⁹ -C (= O) -X ¹ , wherein R ⁹ and -X ¹ have the same meaning as previously defined using a standard peptide addition procedure such as that described above? ~

1

Compounds of formula (IV) wherein R, R, A '' and Z have the same meaning as previously defined,

A 1 A

Y is -CO ₂ R 6. (in which R has the same meaning as defined above) and ΐΛ is _-CH-CH2 - (or _-CH-CH2 -)

I 1 nh ₂ nh ₂ can be prepared by hydrogenation of the corresponding derivatives of the general formula IV in which L ¹ represents a group

- 204 -CH-CH ₂ -

I _:

N (CH ₂ Ph) ₂ (or "CH" CH "

CH,

Ph Ph

This reaction may be carried out in the presence of formic acid and a suitable metal catalyst, such as palladium, supported on an inert support material such as carbon at a temperature of about 60 ° C. The reaction may conveniently be carried out in the presence of a suitable metal catalyst, such as platinum or palladium optionally deposited on an inert support material, such as carbon, preferably in a solvent such as methanol or ethanol.

Compounds of formula (IV) wherein R, R, A and tA have the same meaning as previously defined,

Y is -CO ₂ R ¹⁶ (wherein R ¹⁶ has the same meaning as previously defined) and iA is -CH-CH ₂ nh ₂ (or

CH — CH — nh ₂

205 can also be obtained from the corresponding racemic mixture by standard recrystallization of a suitable salt (such as tartrate salt recrystallization) or by applying standard enzymatic cleavage techniques (e.g., Soloshonok, VA et al., Tetrahedron, as. 7, 1601-1610).

Compounds of formula (IV) in which R, R, A and Z * have the same meaning as previously defined,

-i / 1 <

Y is -CO ₂ R ° (in which R ° has the same meaning as previously defined) and ΐΛ is -CH-CH ₂ -

N (CH ₂ Ph) ₂ (or

CH,

CH

AND

Ph

-CH — CHI

Γ ²

Ph can be prepared by reacting an ester of a compound of formula IV wherein R, R, A and Z are as defined above, Y is -CO ₂ R 6 (wherein R ⁴ is as defined above) ) and ΐΛ represents a group -CH = CH-, with an alkali metal hydride such as sodium hydride in an inert solvent such as tetrahydrofuran and at a temperature approximately equal to room temperature, followed by reaction with an anion derived from the dibenzylamine treatment; or

(S) -N-Benzyl-α-methylbenzylamine with butyllithium at about -78 ° C.

4

Compounds of formula (IX) wherein R, R and X. have the same meaning as previously defined, A 1 is methylene and z 2 is C (= O) can be prepared using or adapting the methods described in Bourlot A.S. et al., Synthesis, 1994, 4, 411-416.

4

Compounds of formula (IX) in which R, R and X have the same meaning as previously defined, A 1 represents an ethylene group and z 2 represents a C (= O) group may be prepared using or adapting the methods described in U.S. Patent No. 5,368,549. 4,421,918.

and

The intermediates of formula (IV), (IX) and (2) are novel compounds and therefore compounds that fall within the scope of the patent protection of the present invention as well as processes for their preparation.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the preparation, the intermediate aspects and the aspects will be further but of the invention.

of the present invention, their procedures and their efficacy tests, and others are explained in more detail by way of examples, not to be construed as limiting the scope thereof.

In the case of nuclear magnetic resonance spectra (NMR), chemical shifts were expressed in ppm relative to tetramethylsilane. Use of the abbreviation has the following meaning:

• ·

- 207 s = singlet, d = doublet, t = triplet, m = multiplet.

The mass spectrum (MS) used in Example 4 (b) and the Reference Examples (unless otherwise noted) was recorded on a Micromass Platform II mass spectrometer connected to an Electrospray source and an HP1100 liquid chromatograph using a mixture of acetonitrile and water (v / v). 1: 1 ratio) as the mobile phase, with a flow rate of 0.3 milliliters / minute, injection volume of 20 μΐ, assay time of 2.0 minutes, scan range 150-850 daltons (positive / negative), scan time 2, 0 seconds, ESI voltage 3.5 kV, ESI pressure 20n / m2 nitrogen.

Mass spectra [MS (ES ⁺ )] in Examples 1 to 12 were recorded on a Micromass LCT Mass Spectrometer, with an atmospheric pressure Z-flow ionization source operating in positive ion electrospray mode (ES ^+). ), which was connected to the HP1100 liquid chromatograph. The conditions used were as follows:

Luna C1 8-H-PLG-3-Microns (30mL im x 4.6 _____ millimeter) operating under gradient elution conditions with a mixture of acetonitrile and water as the mobile phase gradient:

0.00 minutes, 95% water: 5% acetonitrile,: 95% acetonitrile,

95% acetonitrile: 5% acetonitrile, flow rate 2 ml (minute with approximately 200 ml / minute by mass spectrometer injection, 10 to 40 ml injection volume, in-line diode detection (220-450 nm), in-line detection -line light scattering (ELS), ELS detection: temperature 50 ° C, Gain 8 to 1.8

4.50 minutes, 5% water 5.00 minutes, 5% water, 5.50. minutes, 95% water

milliliters / minute, source temperature 150 ° C.

Example 1

3- (1 - {[3-methoxy-4- (3- [2-methylphenyl] -ureido) -phenyl] -acetyl} -1,2,3,4-tetrahydro-quinolin-6-yl) -propionic acid

A solution containing ethyl 3- (1 - {[3-methoxy-4 - [(2-toluidino-carbonyl) amino] phenyl} acetyl) -1,2,3,4-tetrahydroquinoline6- yl) -propanoic acid (0.24 g, see Reference Example 1), in anhydrous ethanol (4 ml) at a temperature of 0 ° C, which was treated with a solution of lithium hydroxide nohohydrate (33 milligrams) in distilled water (1 ml) drop by drop. The resulting solution was stirred for 3 hours at 20 ° C, then the reaction mixture was evaporated under reduced pressure (2.7 kPa) at 40 ° C. The residue was treated with distilled water (35 mL) and the resulting solution was washed twice with diethyl ether (20 mL), then acidified to pH 3 by addition of "hydrochloric acid" (0.8 mL, 1 N solution) and extracted. twice with ethyl acetate (25 mL). The combined organic extracts were washed twice with water (5 mL), dried over magnesium sulfate and then evaporated under reduced pressure (2.7 kPa) at 40 ° C. The resulting foam solid (191 mg) was subjected to silica gel chromatography plates (4 plates, 20 x 20 centimeters, 0.5 mm thickness), eluting with a mixture of dichloromethane and methanol (9: 1 by volume). to give the title compound as a white foam solid.

Yield: 148 mg.

209 ¹ H NMR (300 MHz, (CD ₃ ) ₂ SO): δ

1.81 (m, 2H), 2.27 (s, 3H), 2.45-2.70 (m, 4H),

2.82 (t, J = 7.5Hz, 2H), 3.72 (t, J = 6.5Hz, 2H),

3.82 (s, 2H), 3.87 (s, 3H), 6.60-7.50 (m, 8H),

7.82 (d, J = 8Hz, 1H), 8.05 (d, J = 8Hz, 1H),

8.50 (s, 1H), 8.60 (s, 1H).

MS (electron impact recorded on a Finnigan SSQ 7000 spectrometer at 70 eV) 501 (M ⁺ )

Example 2 (a) (R / S) 3- (1 - {[3-Methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl} -2,3-dihydro-1H-indole- 5-yl) -butyric acid

A solution containing (R / S) 3- (1 - {[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl} -2,3-dihydro-1H-ethyl ester was used. (indol-5-yl) butyric acid [2.8 grams, see Reference Example 4 (a)] in methanol (approximately 150 mL) was treated with aqueous sodium hydroxide solution (1 M solution, 15 µm). The reaction mixture was heated at about 50 ° C for 3 hours and then treated with another aliquot of aqueous sodium hydroxide (7.5 mL). After an additional 2 to 3 hours at 50 ° C, TLC analysis showed that the reaction was complete. The methanol was removed by evaporation and the residue was diluted with hydrochloric acid (approximately 200 ml, 1 M solution). The resulting mixture was stirred for about 30 minutes, then the solid was collected by filtration, washed with water and dried to give the title compound. in the form of a very light orange-colored powder.

Yield: 2.3 g.

- 210 LC-MS: R _T = 3.84 minutes (100% of total EPP area)

MS (ES ⁺ ) 502 (MH &lt; ⁺ &gt;), 524 (MNa &lt; ⁺ & gt ^; ).

(b)

In a similar manner to that described in Part 2 (a) above, but using ethyl ester (R / S)

3- {1 - [(2-o-tolylamino-3H-benzimidazol-5-yl) -acetyl] 1,2,3,4-tetrahydroquinolin-6-yl} -butyric acid [see Reference Example 4 (k)] and hydrolysis at room temperature gave (R / S) 3- {1 - [(2-o-tolylamino-3H-benzimidazol-5-yl) -acetyl] -1,2,3,4-tetrahydroquinolin-6-yl} - Butter in the form of a white solid.

Analysis for ^C 30 ^H 31 ^N 3 ° 4 · ⁵ ' ^5H 2 °

H, 6.32; N, 8.30

Found: C, 71.11; H, 6.55; N, 8.66

MS (ES ^&lt; ^{+ &gt;} ) 498 (MH ^&lt; ^{+ &gt;} ).

(C)

The procedure of this embodiment was carried out in a similar manner to that described in Section 2 (a) above, but with the exception of:

- use - 1 - suspension - ethyl ester (R / S) ___________

3- (1 - {[3-methoxy-4- (3-o-tolylureido) -phenyl] -acetyl} -2,3-dihydro-1H-indol-5-yl) -heptane [see Reference Example 4 (p )], the reaction being carried out in an industrially methylated alcohol at 80 ° C for 45 minutes to obtain the desired (R / S) 3- (1 - {[3-methoxy-4- ( 3-o-tolylureido) -phenyl] -acetyl} -2,3-dihydro-1H-indol-5-yl) -heptanoic acid as a white solid.

LC-MS (using formic acid in acetonitrile at a volume concentration of 0.1 to replace acetonitrile for gradient elution): R-p = 4.31 minutes (100% total ELS area);

211 • · • · ··· ··

999 99 ··

9 * • · · · ···. »»

MS (ES ⁺ ) 544 (MH &lt; ⁺ &gt;), 566 (MNa &lt; ⁺ & gt ^; ).

(d)

The procedure was carried out in a similar manner to that described in Part 2 (a) above, but using (R / S) 3 - [- ({4 - [(2,3-dihydroindole-1-carbonyl) - amino] -3-methoxyphenyl} -acetyl) -2,3-dihydro-1H-indol-5-yl] -heptanoic [see Reference Example 4 (q)], wherein the reaction was carried out in an industrially methylated alcohol at 80 ° C for 45 minutes and the desired (R / S) 3 - [- ({4 - [(2,3-dihydro-indole-1-carbonyl) -amino] -3-methoxyphenyl} acid) was obtained as described above. (acetyl) -2,3-dihydro-1H-indol-5-yl] heptane as a white powder.

LC-MS: (using 0.1% v / v acetonitrile to replace acetonitrile for gradient elution) Ry = 4.47 minutes (100% total ELS area);

MS (ES ⁺ ) 556 (MH &lt; ⁺ &gt;), 578 (MNa &lt; ⁺ & gt ^; ).

_(E)_____________________________._____________________

The procedure was carried out in a similar manner to that described in Part 2 (a) above, but using (R / S) 3- (1 - {[3-methoxy-4- (3-o-tolylureido) ethyl ester) - phenyl] -acetyl} -2,3-dihydro-1H-indol-5-yl) -pentanoic [see Reference Example 4 (r)], wherein the reaction was refluxed for 1 hour and above the desired acid (R / S) 3- (1 - {[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl} -2,3-dihydro-1H-indole was obtained as described above -5-yl) pentano in the form of a light yellow-brown color. LC-MS: R _T = 3.01 minutes;

MS (ES ⁺ ) 538 (MNa &lt; ⁺ & gt ^; ).

- 212 · 4 · 4 4 4 4 4 4 * 4 '·

4 4 4 '' · 444444 · 9 '* .9 4 · ♦ «<• 4 4 4 · 4 4 4 (f)

The procedure was carried out in a similar manner to that described in Part 2 (a) above, but using (R / S) 3 - [- ({4 - [(2,3-dihydro-indole-1-carbonyl) ethyl ester] (amino) -3-methoxyphenyl} -acetyl) -2,3-dihydro-1H-indol-5-yl] pentanoic acid [see Reference Example 4 (s)], wherein the reaction was carried out in an industrially methylated alcohol at a temperature of 80 ° C for 45 minutes to give (R / S) 3 - [- ({4 - [(2,3-dihydro-indole-1-carbonyl) -amino] -3- methoxyphenyl} acetyl) -2,3-dihydro

-1H-indol-5-yl] pentanoic acid as a white powder.

LC-MS: (using formic acid in acetonitrile at a volume concentration of 0.1 to replace acetonitrile for gradient elution) Ry = 4.17 minutes (100% total ELS area);

MS (ES ⁺ ) 528 (MH &lt; ⁺ &gt;), 550 (MNa &lt; ⁺ & gt ^; ).

(g) The procedure of this embodiment was carried out in a similar manner to that described in Part 2 (a) above, but using (R / S) 3- (1 - {[3-methoxy-4- (3) -ethyl ester] -o-tolyl-ureido) -phenyl] -acetyl} -2,3-dihydro-1H-indol-5-yl) -3-phenylpropionic [see Reference Example 4 (s)], the reaction being carried out at boiling point below reflux for 1 hour to give the desired acid (R / S) as described above.

3- (1 - {[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl} -2,3-dihydro-1H-indol-5-yl) -3-phenylpropionic acid white solids.

LC-MS: R y = 3.17 minutes;

MS (ES ⁺ ) 564 (MH &lt; ⁺ &gt;), 586 (MNa &lt; ⁺ & gt ^; ).

· · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- 213 - * · 2 2 * * * h h h h h

The procedure was carried out in a similar manner to that described in Part 2 (a) above, but using (R / S) 3 - [- ({4 - [(2,3-dihydro-indole-1-carbonyl) -ethyl ester] (amino) -3-methoxy-phenyl} -acetyl) -2,3-dihydro-1H-indol-5-yl] -3-phenylpropionic acid [see Reference Example 4 (u)], wherein the reaction was carried out in an industrial environment methylated alcohol at 80 ° C for 90 minutes to give the desired (R / S) 3 - [- ({4 - [(2,3-dihydro-1H-indole-1-carbonyl) acid] (amino) -3-methoxyphenyl} acetyl) -2,3-dihydro-1H-indol-5-yl] -3-phenylpropionic acid as an off-white powder.

LC-MS: (using formic acid, in acetonitrile at a volume concentration of 0.1 k-replacing acetonitrile for gradient elution) Ry = 4.27 minutes (100% of total ELS area);

MS (ES ⁺ ) 576 (MH &lt; ⁺ &gt;), 598 (MNa &lt; ⁺ & gt ^; ). ______ Example ____ 3_________ _b ____________, _ ___ (a) (R / S) 3- (1 - {[4- (3-o-tolyl-ureido) -phenyl] -2-acetyl} -2,3-dihydro-1H-indole -5-yl) -butyric

A mixture containing (R / S) 3- (1 - {[4- (3-o-tolyl-ureido) -phenyl] -acetyl} -2,3-dihydro-1H-indole- 5-yl) -butyrate [0.55 g, see Reference Example 4 (b)], aqueous sodium hydroxide solution (5.5 ml, 1 M solution), methanol (5.5 ml) and tetrahydrofuran (11 ml), The reaction mixture was stirred at room temperature overnight and then evaporated to a small volume. The residue obtained

214 * · · j j 4 ‘‘ β β j

-. 9 ft. 444 was diluted with water and the mixture was then acidified by the addition of hydrochloric acid. The precipitate was removed by filtration, washed with water and then dried to give the title compound as a white powder.

Yield: 0.41 g,

LC-MS: R _T = 3.77 minutes (100% total area by ELS); MS;

(ES ⁺ ) 472 (MH &lt; ⁺ &gt;), 494 (MNa &lt; ⁺ & gt ^; ).

(b)

The procedure was carried out in a similar manner to that described in Part 3 (a) above, but using (R / S) 3- (1 - {[3-methoxy-4- (3-o-tolylureido) ethyl ester) - phenyl] -acetyl} -1,2,3,4-tetrahydroquinolin-6-yl) -butyric acid [see Reference Example 4 (e)] to prepare (R / S) acid

3- (1 - {[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl} -1,2,3,4-tetrahydroquinolin-6-yl) -butyric acid as a white powder. "

LC-MS: R y = 3.89 minutes (100% of total ELS area);

MS (ES ⁺ ) 516 (MH &lt; ⁺ &gt;), 538 (MNa &lt; ⁺ & gt ^; ). ____________ (c)

The procedure was carried out in a similar manner to that described in Part 3 (a) above, but using (R / S) 3- (1 - {[4- (3-o-tolyl-ureido) -phenyl] -ethyl] -ethyl ester -acetyl} -1,2,3,4-tetrahydroquinolin-6-yl) -butyric acid [see Reference Example 4 (f)] to give (R / S) 3- (1 - {[4- (3-o-tolylureido) -phenyl] -acetyl} -1,2,3,4-tetrahydroquinolin-6-yl) -butyric acid as a white solid.

LC-MS: R y = 2.92 minutes (100% of total ELS area);

MS (ES ⁺ ) 508 (MNa &lt; ⁺ & gt ^; ).

215 d

The procedure was carried out in a similar manner to that described in Part 3 (a) above but using 3- {1 - [(2-o-tolylamino-benzoxazol-6-yl) -acetyl] -1,2-ethyl ester 3,4-tetrahydroquinolin-6-yl} -butyric acid [see Reference Example 4 (g)] to give (R / S) 3- {1 - [(2-o-tolylaminobenzoxazol-6-yl) acid 1-Acetyl] -1,2,3,4-tetrahydro-quinolin-6-yl} -butyric acid in the form of a colorless foam.

LC-MS: R _T = 3.01 minutes (100% total area by ELS);

MS (ES ⁺ ) 484 (MH &lt; ⁺ &gt;), 506 (MNa &lt; ⁺ & gt ^; ).

Example 4 (a) 3- (1 - {[3-Methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl} -2,3-dihydro-1H-indol-5-yl) - pentanedio

A stirred suspension containing 3- (1 - {[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl} -2,3-dihydro-1H-indole- 5-yl) pentanedio [270 milligrams, see Reference Example 4 (c)] in ethanol (10 mL), treated with a solution of sodium hydroxide (190 mL) in water (2 mL) and stirred at reflux temperature for 3 hours. After cooling to room temperature, the mixture was treated with water (10 mL) and then carefully acidified to pH 1 by addition of hydrochloric acid (3 M solution) while cooling in an ice bath. The resulting precipitate was collected by filtration, dried, and recrystallized from ethyl acetate to give the title compound as a white solid.

4 9 * 4 · 4 4

4 49 4 4 4 4444 4> 9 4 4

1. * ft 4 * 4 4 4 * 4 9 4 44 4

216 crystalline solids.

Yield: 60 mg.

LC-MS: R y = 2.44 minutes (100% of total ELS area);

MS (ES ⁺ ) 568 (MNa &lt; ⁺ & gt ^; ).

(b)

The procedure was carried out in a similar manner to that described in Section 4 (a) above, but using 3- (1 - {[4- (3-o-tolyl-ureido) -phenyl] -acetyl} -2-dimethyl ester) 3-dihydro-1H-indol-5-yl) pentanedioic acid [see Reference Example 4 (d)] to give 3- (1 - {[4- (3-o-tolyl-ureido) acid - phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) pentanedioic acid as a white solid.

MS (ES ^- ) 514 (M ^- ). (c) ·. ·· *

The procedure was carried out in a similar manner to that described in Section 4 (a) above, but using 3- (1 - {[3-methoxy-4- (3-o-tolylureido) -phenyl] -acetyl) dimethyl ester. 1,2,3,4-tetrahydro-quinolin-6-yl) -pentanedio [see Reference Example 4 (h)], the product obtained was subjected to flash chromatography on a silica gel column using a methanol / dichloromethane ( (1: 9 by volume) as eluent to give 3- (1 - {[3-methoxy-4- (3-o-tolylureido) -phenyl] -acetyl} -1,2,3, 4-tetrahydroquinolin-6-yl) pentanedioic acid as a white foam.

LC-MS: R-p = 2.40 min (100% of total ELS area);

MS (ES ⁺ ) 582 (MNa &lt; ⁺ & gt ^; ).

- 217 *

4 t. (D)

The procedure was carried out in a similar manner to that described in Section 4 (a) above, but using (R) 4- [2-methoxycarbonyl-1- (1 - {[3-methoxy-4- (3-) methyl ester]). o-tolylureido) -phenyl] -acetyl} -1,2,3,4-tetrahydroquinolin-6-yl) -ethylcarbamoyl] -butyric acid [see Reference Example 4 (i)], the product obtained was subjected to flash chromatography in column packed with silica gel using methanol / dichloromethane (1: 9 by volume) as the eluent to give (R) 4- [2-carboxy-1- (1 - {[3-methoxy-4- (3-o-tolylureido) -phenyl] -acetyl} -1,2,3,4-tetrahydroquinolin-6-yl) -ethylcarbamoyl] -butyric acid as a white powder.

LC-MS: R y = 2.43 min (100% of total ELS area);

MS (ES ⁺ ) 653 (MNa &lt; ⁺ & gt ^; ).

(E)

The procedure was carried out in a similar manner to that described in Section 4 (a) above, but using methyl amide (R) methyl ester.

N- [2-methoxycarbonyl-1- (1 - {[3-methoxy-4- (3-o-tolylureido) -phenyl] acetyl} -1,2,3,4-tetrahydroquinolin-6-yl) -ethyl] -succinate [see Reference Example 4 (j)], the product obtained was subjected to flash column chromatography on a silica gel column using methanol / dichloromethane (1: 9 by volume) as eluent to give the title compound as a white solid, m.p. (R) N- [2-carboxy-1- (1 - {[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl} -1,2,3,4- tetrahydroquinolin-6-yl) -ethyl] -succinate in the form of a colorless gum.

LC-MS: R y = 2.44 minutes (100% of total ELS area);

MS (ES ⁺ ) 639 (MNa &lt; ⁺ & gt ^; ).

0 ·

0 «

218

Example 5 (R / S) 1- (4- {2-Oxo-2- [6- (2-oxo-tetrahydro-pyran-4-yl) -3,4-dihydro-2H-quinolin-1-yl] -ethyl (phenyl) -3-o-tolyl-urea.

0Ϊ •

• 0 ·

A solution containing [4- (3-o-tolylureido) -phenyl] -acetic acid (310 milligrams), diisopropylethylamine (310 milligrams) and dimethylformamide (5 milliliters) was treated sequentially with O- (7-azabenzotriazole). -1-yl) -Ν, Ν, Ν ', N'-tetrametbyluronium hexafluorophosphate (450 mg) and then (R / S) 4- (1,2,3,4-tetrahydroquinolin-6-yl) -tetrahydro- pyran-2-one [250 milligrams, see Reference Example 5 (c)]. The reaction mixture was allowed to stand at room temperature for 2 hours and partitioned between ethyl acetate (100 mL) and dilute hydrochloric acid (100 mL). The layers were separated and the organic phase was washed with water, dried and evaporated. The residue was subjected to flash chromatography on a silica gel column using ethyl acetate as eluent to give a yellow gum. The product was dissolved in a minimum volume of ethanol and treated with ether to give a yellow solid which was collected by filtration and dried to give the title compound as a yellow solid. Yield: 80 mg.

LC-MS: Rrp = 3.74 minutes (100% of total ELS area);

MS (ES ⁺ ) 520 (MNa @ ⁺ ).

Example 6

(R) 3- (1 - {[3-Methoxy-4- (3-o-tolyl-ureido) -phenyl] -phenyl] 219

-acetyl} -1,2,3,4-tetrahydroquinolin-6-yl) -3 - [(5-methyl-isoxazole-3-carbonyl) -amino] -propionic acid

(R) 3- (1-boc-1,2,3,4-tetrahydro-quinolin-6-yl) -3 - [(5-methyl-isoxazole-3-carbonyl) -methyl ester was used in the procedure. 1-amino] -propionic acid [310 milligrams, see Reference Example 17], which was dissolved in a mixture of trifluoroacetic acids and dichloromethane (1: 1 by volume), the clear solution was allowed to stand at room temperature for 2 hours. The residue obtained after evaporation of this solution was added to a mixture containing [3-methoxy-4- (3-o-tolylureido) -phenyl] -acetic acid (280 mg), O- (7-azabenzotriazol-1-yl) -Ν , Ν, Ν ', N'-tetramethyluronium hexafluorophosphate (340 milligrams) and diisopropylethylamine (1 ml) in dimethylformamide (30 ml). The resulting mixture was then allowed to stir at room temperature for 3 hours and then allowed to stand overnight. The mixture was evaporated to a small volume and the residue was partitioned between ethyl acetate and dilute chloroylic acid solution. The layers were separated and the organic layer was washed with sodium carbonate solution, dried and evaporated to give 580 mg of an orange oil. Purification by flash chromatography using 1: 1 ethyl acetate / dichloromethane as eluent gave the product as an orange foam. This product was dissolved in methanol (20 mL) and treated with 1.0 M sodium hydroxide solution. After heating at reflux for 2 hours, the resulting mixture was evaporated to a small volume and the residue was diluted with water. The mixture was then acidified with dilute hydrochloric acid solution to afford

220 obtained a gummy product which was extracted into an ethyl acetate solution. The solution was dried and evaporated to give the title compound as a pale yellow foam. Yield: 110 mg.

LC-MS: R t = 2.94 minutes (100% of total ELS area);

MS (ES ⁺ ) 648 (MNa &lt; ⁺ & gt ^; ).

Example 7 (a) (S) 2- (2-Chloro-6-methyl-benzoylamino) -3- [1- (2,6-dichloro-benzoyl) -1,2,3,4-tetrahydroquinolin-6- yl] -propionic.

A mixture containing (S) 2-amino-3- [1- (2,6-dichloro-benzoyl) -1,2,3,4-tetrahydroquinolin-6-yl] -propionic acid methyl ester [200 milligrams, see 200 mg. Reference Example 18], O- (7-azabenzotriazol-1-yl) -Ν, Ν, Ν ', N'-tetramethyluronium hexafluorophosphate (200 milligrams) and 2-chloro-6-methylbenzoic acid (90 milligrams) in dimethylformamide which was The reaction mixture was partitioned between ethyl acetate (50 mL) and dilute hydrochloric acid (50 mL). The resulting solution was allowed to stand at room temperature overnight. The organic phase was then washed with sodium bicarbonate solution, dried and evaporated. The residue was then analyzed by thin-layer chromatography on silica gel, eluting with ethyl acetate / dichloromethane (1: 9, v / v) to give very close spots of approximately the same intensity. The product was subjected to work-up

221 ”« · ···· · · · · · · ·

Flash chromatography on silica gel, eluting with ethyl acetate / dichloromethane (1: 9 by volume): the volume of fractions contained mixed spots, but separated fractions containing each pure component were obtained. On standing in solution for more than about one hour, each pure component was transformed into an identical mixture of the two components, indicating that both spots were represented by stable rotamers. Accordingly, all fractions containing either one or both spots were combined and evaporated to give a colorless oil (160 mg). This material was dissolved in methanol (10 mL) and treated with lithium hydroxide solution (1 M solution, 4 mL). The mixture was allowed to stand at room temperature for 30 minutes, then evaporated to a small volume and the residue dissolved in water (10 ml). Acidification with dilute hydrochloric acid gave a white precipitate which was collected by filtration, washed with water and then dried to give the title compound as a white solid.

Yield: 105 mg.

LC-MS: (indicated as a mixture of two stable rotamers): 1Ry rotamer = 2.79 minutes (57% of total ELS area);

MS (ES ⁺ ) 567, 569 (MNa &lt; ⁺ & gt ^; );

rotamer 2: Ry = 3.96 minutes (43% of total ELS area);

MS (ES ⁺ ) 567, 569 (MNa &lt; ⁺ & gt ^; ).

(b)

The procedure was carried out in a similar manner to that described in Section 7 (a) above, but using tetrahydropyran-4-carboxylic acid to give (S) 3- [1- (2,6-dichloro222)]. · · ♦ .. · · 9 9 9 9 9

-benzoyl) -1,2,3,4-tetrahydroquinolin-6-yl] -2 - [(tetrahydropyran-4-carbonyl) -amino] -propionic acid as a white powder.

LC-MS: (indicated as a mixture of two stable rotamers): rotamer 1: Ry = 2.47 minutes (52% of total ELSD area);

MS (ES ⁺ ) 527 and 529 (MNa ⁺ );

rotamer 2: R _T = 2.66 minutes (48% of total ELS area);

MS (ES ⁺ ) 527 and 529 (MNa ⁺ ).

Example 8

(S) 2- (2,6-dichloro-benzoylamino) -3- [1- (2,6-dichloro-benzoyl) -1,2,3,4-tetrahydroquinolin-6-yl] -propionic acid.

A solution containing (S) 2-amino-3- [1- (2,6-dichlorobenzoyl) -1,2,3,4-tetrahydroquinolin-6-yl] -propionic acid methyl ester (180 mg, see Reference Example 18) in dichloromethane (10 mL) which was treated with diisopropylethylamine (150 milligrams) and then 2,6-dichlorobenzoyl chloride (130 milligrams). The product was allowed to stand at room temperature overnight and the mixture was partitioned between ethyl acetate (50 mL) and dilute hydrochloric acid (50 mL). The organic phase was then washed with sodium bicarbonate solution, dried and evaporated. The residue was subjected to flash chromatography on silica gel, eluting with ethyl acetate / dichloromethane (1: 9, v / v) to give a colorless oil (160 mg). This material was treated with methanol (10 mL) followed by lithium hydroxide solution (1 M solution, 4 mL). The mixture was allowed to stand at room temperature for one hour, after which time it was allowed to cool

The mixture was evaporated to a small volume and the residue was dissolved in water (10 mL). This solution was then acidified by the addition of dilute hydrochloric acid. The resulting white precipitate was filtered and then washed with water and then dried to give the title compound as a white solid.

Yield: 120 mg.

LC-MS: (indicated as a mixture of stable rotamers):

Rotameter 1: Ry = 2.79 minutes (48% of total ELS area);

MS (ES ⁺ ) 587.599 (MNa ⁺ );

rotamer 2: Ry = 3.74 minutes (10% of total ELS area);

MS (ESI +) 587, 589 (MNa ⁺ );

rotamer 3: Ry = 3.96 minutes (46% of total EPP area)

MS (ES ⁺ ) 587.599 (MNa ⁺ ).

Example 9

(R / S) 3- [1 - ({4 - [(2,3-Dihydroindole-1-carbonyl) -amino] -3-methoxy-phenyl} -acetyl) -1,2,3,4-tetrahydroquinoline -6-yl] -butyric acid

Bromo-Vang resin (1 gram, nominal 1 mmol / g, Novabiochem) was suspended in dimethylformamide (15 ml) and then treated sequentially with 9H-fluoren-9-ylmethyl ester (R / S) 6- (2-carboxy-1-methyl-ethyl) -3,4-dihydro-2H-quinoline-1-carboxylic acid (880 milligrams, Reference Example 28) in dimethylformamide (5 ml), diisopropylethylamine (0.35 ml) and cesium iodide (270 milligrams). The reaction mixture was then allowed to stand at room temperature overnight with occasional shaking. The resin was then drained and washed with (i)

224 five times with dimethylformamide, (ii) three times with water, (iii) five times with dimethylformamide, (iv) three times with methanol, (v) four times with dichloromethane, and (vi) two times with ether, and finally dried.

Stage 2:.

The resin obtained in Step 1 was then suspended in a mixture of piperidine and dimethylformamide (20 ml, 1: 4 by volume) and the mixture was kept at room temperature for about 2 hours with occasional shaking. The resin was then dewatered and then washed (i) five times with dimethylformamide, (ii) three times with methanol, (iii) four times with dimethylformamide, (vi) twice with ether, and dried.

Stage 3: ‘

The resin of Step 2 was then suspended in dimethylformamide (15 mL) and treated sequentially with O- (7-azabenzotriazol-1-yl) N, N-N-H-tetramethylhururium hexafluorophosphate (570 mg), {4 - [( 2,3-dihydroindole-1-carbonyl) amino] -3-methoxyphenyl} -acetic acid (490 mg) and diisopropylethylamine (0.52 ml) were finally allowed to stand at room temperature overnight with occasional shaking. The resin was first dewatered and then washed (i) five times with dimethylformamide, (ii) three times with methanol, (iii) four times with dimethylformamide, and (vi) twice with ether, and dried.

Stage 4:

The resin obtained in Step 3 was treated with the mixture

225 trifluoroacetic acid and dichloromethane (about 10 mL; 1: 1 by volume) and the mixture was then kept at room temperature for about 1 hour with occasional shaking. The resin was then dewatered and washed with a mixture of trifluoroacetic acid and dichloromethane (1 mL, 1: 1 by volume). The combined filtrates were evaporated and the residue obtained as a brown oil was treated with dilute sodium hydroxide solution. The resulting aqueous solution was washed with ether and then with dichloromethane and acidified by the addition of hydrochloric acid. The precipitated product was extracted four times with dichloromethane. The combined extracts were dried and then evaporated. The residue was then triturated with ether to give the title compound as a cream solid.

Yield: 120 mg.

LC-MS: R _T = 3.16 min (100% of total ELS area);

MS (ES ⁺ ) 550 (MH ⁺ ). Example 10 ----- L —_______-; -____

(S) 2-Acetylamino-3- (1 - {[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl} -1,2,3,4-tetrahydroquinolin-6-yl ) -propionic.

* H

A solution containing (S) 2-acetylamino-3- (1 - {[3-methoxy-4- (3-o-tolylureido) -phenyl] -acetyl} -1,2,3,4-methyl ester was used -tetrahydroquinolin-6-yl) -propionic acid [(220 milligrams, see Reference Example 4 (1)] in dioxane (3 milliliters) which was treated with a solution of lithium hydroxide hydrate (50 milligrams) in water (1 milliliter). The mixture was stirred at room temperature for 3 hours and then worked up

• · · · · · · · · '··· _ν · · · · · • · 9

99 '· 9

9 9

Water (5 ml) and then acidified to pH 1-2 with dilute hydrochloric acid (while cooling on ice). The resulting precipitate was extracted three times with ethyl acetate, the extracts were combined and the combined extracts washed with water and then brine, dried and then evaporated. The residue was recrystallized from ethyl acetate to give the title compound as a white powder.

Yield: 21 mg.

LC-MS: R y = 2.77 minutes (100% of total ELS area);

MS (ES ⁺ ) 581 (MNa &lt; ⁺ & gt ^; ).

Example 11

(R / S) 3- (1 - {[3-Methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl} -2,3-dihydro-1H-indol-5-yl acid sodium salt ] Buttery.

A solution containing (R / S) 3- (1 - {[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl} -2,3-dihydro-1H- indol-5-yl] -butyric acid (2.1

150 grams of methanol which was treated with exactly one equivalent of 0.1 M sodium hydroxide solution. The methanol was evaporated and the residue was diluted with water (120 mL) and lyophilized. The lyophilized portion was then triturated with ether and the insoluble material was washed with ether and then with pentane and dried to give the title compound as an off-white, free-flowing powder. Yield: 1.9 g.

MS (ES ^&lt; ^{+ &gt;} ) 525 (MH ^&lt; ^{+ &gt;} ).

Elementary analysis:

Analysis for .delta. 0.3H ₂ O:

Calculated 60.25% C, 6.20% H, 7.27% N, 9.3% H ₂ 0

- 227 (· (>> · 44 ·; · * · ♦ * · ♦ ♦ · · · · · 4 4 · · '· 44 · <4 · 4 '44 4 4 4- · · ·· '4' 4 4 '4 4 4 ···. ·· 4 4 4 44/4'

Found. 60.01% C, 6.13% H, 7.28% N, 8.25% H ₂ 0th

Example 12 (a) (S) 2- (2,6-dichlorobenzoylamino) -3- {1 - [(2-o-tolylamino-benzoxazol-6-yl) -acetyl] -1,2,3,4- tetrahydroquinolin-6-yl} -propionic acid.

According to this procedure, the acid methyl ester (S) was

2- (N-boc-amino) -3- {1 - [(2-o-tolylamino-benzoxazol-6-yl) -acetyl] -1,2,3,4-tetrahydroquinolin-6-yl} -propionic acid [ 200 mg, Reference Example 4 (m)] was treated with trifluoroacetic acid (3 mL) and the resulting solution was then left at room temperature for 15 minutes and then evaporated. The residue was dissolved in dichloromethane (20 mL) and treated with diisopropylethylamine (260 mg) and then

2,6-dichlorobenzoyl chloride (140 mg). The product was allowed to stand at room temperature overnight and the reaction mixture was evaporated to a small volume

The residue was partitioned between ethyl acetate (50 ml) and dilute hydrochloric acid solution. The organic phase was then washed with sodium bicarbonate solution, dried and evaporated. The residue was subjected to flash chromatography on silica gel, eluting with a mixture of ethyl acetate and dichloromethane (15: 85 by volume). The resulting colorless gum was treated with methanol (10 mL) followed by lithium hydroxide solution (2 mL, 1 M solution). After standing at room temperature for 2 hours, the reaction mixture was evaporated to a small volume, the residue was treated with water (10 ml) and acidified.

- 228 -

, · · * '· • · '· ·. · · · · 9 9 • • 9 • ··· <· » 9 99 9 9 • · 9 • · · 9 9 • • ··· 9 9 9 9 • • ·  9

dilute hydrochloric acid solution. The resulting white precipitate was filtered off, washed with water and then dried to give the title compound as a white powder.

Yield: 90 mg.

LC-MS: R t = 2.97 min (100% of total ELS area);

MS (ES ⁺ ) 657 and 659 (MH ⁺ ), 679 and 681 (MNa ⁺ ), respectively.

(b)

The procedure was carried out in a similar manner to that in Example 12 (a), except that methyl ester (S) was used.

3- [1- (2-chlorobenzoyl) -1,2,3,4-tetrahydroquinolin-6-yl] -2- (N-boc-amino) propionic acid [see Reference Example 4 (n)], and

2-chloro-6-methylbenzoyl chloride to prepare (S) 3- [1- (2-chlorobenzoyl) -1,2,3,4-tetrahydroquinolin-6-yl] -2- (2-chloro-6-methyl) (benzoylamino) propionic acid in the form of a white powder.

LC-MS: R _T = 2.76 minutes (100% total area by ELS);

MS (ES ⁺ ) 533 and 535 (MNa ⁺ ).

(C)

The procedure was carried out in a similar manner to that in Example 12 (a), except that methyl ester (S) was used.

3- {1 - [(4-acetoxy-3-chlorophenyl) acetyl] -1,2,3,4-tetrahydroquinolin-6-yl} -2- (N-boc-amino) propionic acid [see Reference Example 4 ( o)] and 2-chloro-6-methylbenzoyl chloride to prepare acid (S)

3- {1 - [(3-Chloro-4-hydroxy-phenyl) -acetyl] -1,2,3,4-tetrahydro-quinolin-6-yl} -2- (2-chloro-6-methyl-benzylamino) -propionic acid .

LC-MS: R t. = 2.67 minutes (100% of total EPP area);

229

MS (ES ⁺ ) 563 and 565 (MNa ⁺ ).

Reference Example 1

3- [1- (2- {3-Methoxy-4 - [(2-toluidine-carbonyl) -amino] -phenyl} -acetyl) -1,2,3,4-tetrahydro-6-quinolinyl] -propionic acid ethyl ester

A stirred solution containing 3-methoxy-4- [3- (2-methylphenyl) ureido] -phenylacetic acid (0.232 g) was prepared as described in Example 52B of published International Patent Application No. WO 96/22966 ) in anhydrous tetrahydrofuran (5 mL), which was maintained under argon at 20 ° C and treated with 4A (2 grams) powdered molecular sieves, 3- (1,2,3,4-tetrahydro-6) ethyl ester. quinolinyl) propionic (0.115 grams, see Reference Example 2), triethylamine (0.275 milliliters), O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (0.223 grams) and 4- dimethylaminopyridine (6 milligrams). After stirring the reaction mixture at 20 ° C for 1 hour, the reaction mixture was filtered through a pad of celite. The filtrate was evaporated under reduced pressure (2.7 kPa) at 40 ° C and the residue was then treated with ethyl acetate (25 mL). The solution was washed twice with a saturated aqueous ammonium chloride solution (5 ml) and then with water (5 ml), dried over magnesium sulphate and then evaporated under reduced pressure (2.7 kPa) at 40 ° C. The resulting white foamy solid (0.457 g) was then flash chromatographed on silica gel (0.040-0.063 mm) using a mixture of cyclohexane and ethyl acetate (250 mL, v / v) as eluent.

4 '4 4 4

230: 9: 1, then 500 ml (7: 3 v / v), then 1000 ml (4: 6 v / v) to give the title compound as a white foam.

Yield: 0.244 g.

Reference Example 2

3- (1,2,3,4-tetrahydro-6-quinolinyl) -propanoic acid ethyl ester. ·

A stirred mixture containing 3- (6-quinolinyl) propanoic acid ethyl ester (0.3 grams, see Reference Example 3) in hydrochloric acid (3 ml, 0.1 N solution) of 5% rhodium (33 milligrams) in The carbon powder was hydrogenated in a 22 cm stainless steel reactor at 50 bar of hydrogen. After stirring the reaction mixture for 4 hours at 25 ° C, an additional portion of 5% rhodium (30 milligrams) in carbon powder was added and hydrogenation was continued at 50 bar at 25 ° C. for 1 hour. The reaction mixture was then filtered through a pad of Celite and the filter pad was washed with hydrochloric acid (3 mL, 0.1 N solution) and then with ethyl acetate (25 mL). The filtrate and washings were combined and the aqueous phase was decanted from the organic phase. The aqueous phase was then extracted twice with ethyl acetate (25 ml) and combined with the above organic phase. The combined solutions were dried over magnesium sulphate (2.7 kPa) at 40 ° C to give the title compound as a brown oil.

Yield: 0.121 g.

231 ·· ·· · 4 4 4

Reference Example 3

3- (6-Quinolinyl) propanoic acid ethyl ester.

Dimethylformamide (45 milliliters), pyridine (5 milliliters), tetrabutylammonium bromide (250 milligrams), tetrabutylammonium iodide (18.8 milligrams), and 1,2-dibromoethane (0.30 ml) were sequentially introduced into the electrochemical apparatus described in detail above. 15 ml). The thus prepared solution was deoxygenated by bubbling argon through the solution for about 10 minutes. After pre-electrolysis with a current of 125 mA for 30 minutes, the stirred solution was treated with nickel bromide trihydrate (341 milligrams), 6-bromoquinoline (2.6 grams) and ethyl acrylate (3.12 grams). Stirring of this solution was then continued until the components were completely dissolved. The reaction medium was heated to 60 ° C and electrolysis was carried out at a constant current of 250 mA while maintaining the temperature at 60 ° C. After 3 hours of passing 2810 coulombs (i.e. 2.33 Faradays per mole of 6-bromoquinoline) the electrolysis was stopped . The electrolysed solution plus dimethylformamide washings (20 mL) from the electrochemical apparatus and electrode washes were treated with water (250 mL) and extracted three times with heptane (70 mL), ethyl acetate (50 mL) and diethyl ether (50 mL). The combined extracts were concentrated under reduced pressure (2.7 kPa) at 40 ° C. The residual yellow oil (2.78 grams) was subjected to a silica gel pressure chromatography column (40 mm diameter column, 100 grams of Merck silica gel 60 (0.040-0.063 mm)), whereby

- 232 -

• ·

9 9

9999

4 • 4

9

9, using a mixture of cyclohexane, ethyl acetate and 2-propanol (90: 8: 2, then 85/12/3;) under a slight argon pressure (about 30 kPa) to give the title compound as above. compound in the form of a yellowish oil. Yield: 1.92 g.

The electrochemical apparatus used consisted of the following parts: a cylindrical body (50 milliliters) containing the reaction medium and a 10 mm diameter mild steel rod (consumable anota) and a cylindrical nickel foam grid (30 mm diameter), a height of 42.5 millimeters, the surfaces surrounding a volume of approximately 40 milliliters) concentrically oriented around said anode; glass lid provided with 5 drilled holes, central outlet for electrical contact to, anode, four peripheral outlets for electrical contact to cathode, thermometer, argon inlet and coolant inlet with water. The two parts of the electrolyser were connected with a 60 mm internal diameter adapter piece with a flat ground joint to ensure sealing. The reaction medium was maintained under an inert atmosphere by continuously bubbling argon through the electrolyzed solution. The electrodes were connected to a stabilized power supply or intentiostate. In addition, a current integrator was connected in series to the anode circuit. The reaction medium was agitated with a Teflon coated magnetic rod. The body of this electrochemical apparatus can be placed in an oil bath at the desired reaction temperature.

233 • 8 • ·

000 · 0 • 0

0

0 0 0 »0 008 0 · 0 0 ·

* 0 • · 0>

«0’

Reference Example 4 (a) (R / S) 3- (1 - {[3-Methoxy-4- (3-o-tolylureido) -phenyl] -acetyl} -2,3-dihydro-1H-indole- 5-yl) -butyric acid.

A solution containing [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetic acid (2.9 g) and O- (7-azabenzotriazol-1-yl) -N was used. N, N ', N'-tetramethyluronium hexafluorophosphate (3.7 grams) in dimethylformamide (40 ml) was treated with diisopropylethylamine (10 ml), followed by an addition of (R / S) solution after about 30 seconds. ethyl 3- (2,3-dihydro-1H-indol-5-yl) -butyrate [about 2.5 g, Reference Example 5 (a)] in dimethylformamide (10 ml). The resulting clear dark brown solution was kept at room temperature for about one hour, then evaporated to a small volume. The resulting residue was partitioned between water and ethyl acetate, and the organic layer was washed with dilute aqueous sodium bicarbonate solution and then brine, dried, and evaporated. The residual brown gum was flash chromatographed on silica gel using ethyl acetate / gasoline (3: 2 to 3: 1 by volume) to give the title compound as a pale yellow solid. amorphous foam. .

Yield: 2.8 g.

MS (ES ⁺ ) 552 (MNa &lt; ⁺ & gt ^; ).

- 234

44 · «4 · 4« (b)

The procedure was carried out in a similar manner to that in Reference Example 4 (a), except that in this case the addition was carried out with [4- (3-o-tolylureido) -phenyl] -acetic acid and ethyl ester ( R / S) 3- (2,3-dihydro-1H-indol-5-yl) -butyric acid to give (R / S) 3- (1 - {[4- (3-o- tolylureido) -phenyl] -acetyl} -2,3-dihydro-1H-indol-5-yl) -butyric acid as an off-white solid.

MS (ES ⁺ ) 500 (MH &lt; ⁺ &gt;), 522 (MNa &lt; ⁺ & gt ^; ).

MS (ES) 498 (M) &lt; + &gt;.

(C)

The procedure was carried out in a similar manner to that in Reference Example 4 (a), except that in this case the addition was performed with [3-methoxy-4- (3-o-tolylureido) -phenyl] - acetic and dimethyl 2- (2,3-dihydro-1H-indol-5-ylmethyl) pentanedioic acid dimethyl 3- (1 - {[3-methoxy-4- (3- o-tplyl-ureido) -phenyl] -acetyl} -2,3-dihydro-ΪΗ-trans-5-yl-pentanedioic acid as an off-white foam.

MS (ES ⁺ ) 574 (MH &lt; ⁺ &gt;), 596 (MNa &lt; ⁺ & gt ^; ).

(d),

The procedure was carried out in a similar manner to that in Reference Example 4 (a), except that in this case the addition was carried out with [4- (3-o-tolylureido) -phenyl] -acetic acid and dimethyl ester. 2- (2,3-dihydro-1H-indol-5-ylmethyl) pentanedioic acid to give 3- (1 - {[4- (3-o-tolyl235) dimethyl ester];

(ureido) -phenyl] -acetyl} -2,3-dihydro-1H-indol-5-yl) pentanedione in the form of a white foam.

MS (ES ⁺ ) 566 (MNa &lt; ⁺ & gt ^; ).

MS (ES -) 542 (M).

(E)

The procedure of this embodiment was performed in a similar manner to that in Reference Example 4 (a), except that in this case the addition was carried out with [3-methoxy-4- (3-o-tolylureido) -phenyl] - acetic acid and ethyl (R / S) 3- (1,2,3,4-tetrahydro-quinolin-6-yl) -butyric acid ester (see Reference Example 5 (b)) to give (R / S) ethyl ester S) 3- (1 - {[3-methoxy-4- (3-o-tolylureido) -phenyl] -acetyl} -1,2,3,4-tetrahydroquinolin-6-yl) -butyric acid as a yellow gum .

MS (ES ⁺ ) 544 (MH &lt; ⁺ &gt;), 566 (MNa &lt; ⁺ & gt ^; ).

MS (ES) 542 (M) &lt; + &gt;.

(F)

The procedure was carried out in a similar manner to that in Reference Example 4 (except that in this case the addition was performed with [4- (3-o-tolylureido) -phenyl] -acetic acid and ethyl ester). (R / S) 3- (1,2,3,4-tetrahydro-quinolin-6-yl) -butyric acid [see Reference Example 5 (b)] to give (R / S) 3 ethyl ester - (1 - {[4- (3-o-tolylureido) -phenyl] -acetyl} -1,2,3,4-tetrahydroquinolin-6-yl) -butyric acid.

(G)

The process of this embodiment was carried out in a similar manner to that of Reference Example 4 (a), however

- 236 * ί

989 9 f

9 · '9 9

With the difference that in this case the addition was carried out with (2-o-tolylamino-benzoxazol-6-yl) -acetic acid and ethyl (R / S) 3- (1,2,3, 4-tetrahydro-quinolin-6-yl) -butyric acid [see Reference Example 5 (b)] to give ethyl ester (R / S)

3- {1 - [(2-o-tolylamino-benzoxazol-6-yl) -acetyl] -1,2,3,4-tetrahydroquinolin-6-yl} -butyric acid.

(h)

The procedure was carried out in a similar manner to that in Reference Example 4 (a), except that in this case the addition was performed with [3-methoxy-4- (3-o-tolyl-ureido) -phenyl acid. acetic acid and dimethyl 3- (1,2,3,4-tetrahydroquinolin-6-yl) -pentanedioate [see Reference Example 9 (b)], the product obtained was subjected to flash chromatography on silica gel eluting with silica gel. of ethyl acetate and gasoline (3: 1 by volume) to give 3- (1 - {[3-methoxy-4- (3-o-tolyl-Y-urido) -4-phenyl] acetyl} dimethyl ester -1,2,3,4-tetrahydroquinolin-6-yl) pentanedioic acid as an off-white foam.

MS (ES ⁺ ) 588 (MH &lt; ⁺ &gt;), 610 (MNa &lt; ⁺ & gt ^; ).

MS (ES) 586 (M +).

(and)

The procedure was carried out in a similar manner to that in Reference Example 4 (a), except that in this case the addition was performed with [3-methoxy-4- (3-o-tolylureido) -phenyl] - acetic acid and (R) 4- [1- (1,2,3,4-tetrahydro-quinolin-6-yl) -2-methoxycarbonyl-ethylcarbamoyl] -butyric acid methyl ester [see Reference Example 13 (a)], obtained product was

-Γ - 237 • Μ · Φ · φ · · ·> ·> ·> ·> ·> ·> · · · · ·

Φ φ φφφ φ. The product was subjected to flash chromatography on silica gel, eluting with methanol / dichloromethane (1:19, v / v) to give (R) methyl ester.

4- [2-methoxycarbonyl-1- (1 - {[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl} -1,2,3,4-tetrahydroquinolin-6-yl) -ethylcarbamoyl] -butyrate in the form of a light orange foam.

MS (ES ⁺ ) 659 (MH &lt; ⁺ &gt;), 681 (MNa &lt; ⁺ & gt ^; ).

MS (ES -) 658 (M -).

(j)

The procedure was carried out in a similar manner to that in Reference Example 4 (a), except that in this case the addition was performed with [3-methoxy-4- (3-o-tolyl-ureido) -phenyl acid. and (R) N- [2-methoxycarbonyl-1- (1,2,3,4-tetrahydroquinolin-6-yl) ethyl] succinic acid [see Reference Example 13 (b)], The product was subjected to flash chromatography on silica gel, eluting with methanol / dichloromethane (1:19, v / v) to give the (- R) - (methyl) -polyamido-acid methyl ester.

N- [2-methoxycarbonyl-1- (1 - {[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl} -1,2,3,4-tetrahydroquinolin-6-yl -ethyl] -succinate in the form of a light orange foam.

MS (ES ⁺ ) 667 (MNa &lt; ⁺ & gt ^; ).

(to)

The procedure was carried out in a similar manner to that in Reference Example 4 (a), except that in this case the addition was performed with (R / S) 3- (1,2,3,4-tetrahydro) ethyl ester -quinolin-6-yl) -butyric [see Reference Example 5 (b)]

238 - 4 • fto • to

And (1-boc-2-o-tolylamino-1H-benzimidazol-5-yl) -acetic acid (Reference Example 22), and the product was subjected to flash chromatography on silica gel, eluting with silica gel. ethyl acetate / hexane (3: 7, v / v) to give (R / S) 3- {1 - [(2-tolylamino-3H-benzimidazol-5-yl) acetyl] -1, ethyl ester, 2,3,4-tetrahydroquinolin-6-yl} -butyrate.

(1)

The procedure was carried out in a similar manner to that in Reference Example 4 ( _a ), except that in this case the addition was performed with [3-methoxy-4- (3-o-tolyl-ureido) -phenyl acid. Acetic acid and (S) 2-acetylamino-3- (1,2,3,4-tetrahydroquinolin-6-yl) -propionic acid methyl ester [see Reference Example 19 (b)], the product obtained was subjected to flash chromatography silica gel, eluting with methanol / dichloromethane (1:19, v / v) to give (S) methyl ester

2-acetylamino-3- (1 - {[3Χπ6ΐΚοχγ ^ 4 ^ “(~ 3 ^ ο-ΐο1-γΤην6Ϊύο) -4-phenyl) ^ -.____

-acetyl} -1,2,3,4-tetrahydroquinolin-6-yl) -propionic acid as an off-white foam.

MS (ES ^&lt; ^{+ &gt;} ) 573 (MH ^&lt; ^{+ &gt;} ), MS (ES ^&lt; ^{- &gt;} ) 572 (M &lt; - &gt;).

(m)

The procedure was carried out in a similar manner to that in Reference Example 4 (a), except that the addition was in this case with (2-o-tolylamino-benzoxazol-6-yl) -acetic acid and methyl ester. 2- (N-boc-amino) -3- (1,2,3,4-tetrahydroquinolin-6-yl) -propionic acid [see Reference Example]

- 239 · 9, »9 9. 9 9. 9 · ’· · 4 i i i i i i i i i i i i i i i i i i i i

19], the product was subjected to flash chromatography on silica gel, eluting with ethyl acetate / dichloromethane (1: 9, v / v) to give the methyl ester (S).

2- (N-boc-amino) -3- {1 - [(2-o-tolylaminobenzoxazol-6-yl) acetyl] -1,2,3,4-tetrahydroquinolin-6-yl} -propionic acid, colorless gums.

(n)

The procedure of this embodiment was performed in a similar manner to that in Reference Example 4 (a), except that in this case the addition was performed with 2-chlorobenzoic acid and methyl ester (S).

2- (N-boc-amino) -3- (1,2,3,4-tetrahydroquinolin-6-yl) -,

-propionic acid (see Reference Example 19), and the product was subjected to flash chromatography on silica gel, eluting with ethyl acetate: dichloromethane (15: 85, v / v) to give the methyl ester (S). ) 3- [1- (2-chloro-benzoyl) -1,2,3,4-tetrahydroquinolin-6-yl] -2- (N-boc-amino) -propionic acid in the form of colorless oils.

(O)

The procedure was carried out in a similar manner to that in Reference Example 4 (a), except that in this case the addition was carried out with (4-acetoxy-3-chlorophenyl) -acetic acid and (S) 2 methyl ester. - (N-boc-amino) -3- (1,2,3,4-tetrahydro-quinolin-6-yl) -propionic acid (see Reference Example 19), the product obtained was subjected to flash chromatography on silica gel, where as elution * «9 · 9 9« · 9 9 · «9

240

9 9 99 * 9 9 9999 9 9 ·. 9 · 9,999 9 · • '99 99 9 «9 · 9'

of ethyl acetate and dichloromethane (15: 85 by volume) to give 3- {1 - [(4-acetoxy-3-chlorophenyl) -acetyl] -1,2,3,4- tetrahydroquinolin-6-yl} -2- (N-boc-amino) propionic acid as a colorless oil.

(p)

The procedure was carried out in a similar manner to that in Reference Example 4 (a), except that the addition was performed with 3-methoxy-4- (3-o-tolyl-ureido) -phenylacetic acid and ethyl (R / S) 3- (2,3-dihydro-1H-indol-5-yl) -heptanoic acid [see Reference Example 24 (a)], the product obtained was subjected to flash chromatography on silica gel, where as ethyl acetate / pentane (11: 9 by volume) to give (R / S) 3- (1 - {[3-methoxy-4- (3-o-tolyl-ureido) ethyl ester) (phenyl) -acetyl} -2,3-dihydro-1H-indol-5-yl) heptane foam.

(q) '- ----—

The procedure was carried out in a similar manner to that in Reference Example 4 (a), except that in this case the addition was performed with 4 - [(2,3-dihydro-1H-indole-1-carbonyl) acid. -amino] -3-methoxy-phenylacetic acid and ethyl ester (R / S)

3- (2,3-dihydro-1H-indol-5-yl) -heptanoic acid [see Reference Example 24 (a)], to give (R / S) 3 - [- ({4- [ (2,3-dihydro-1H-indole-1-carbonyl) -amino] -3-methoxy-phenyl} -acetyl) -2,3-dihydro-1H-indol-5-yl] -heptanoic acid as a white solid .

MS (ES ⁺ ) 606 (MNa &lt; ⁺ & gt ^; ).

241 -

* · '· 9 9 9 4 · * 4 ·· 4 '4 4 9 • 4 9 999 <9 9499 9 4 · 9 9 4 4 9 9 · ·· 4 4 4 • • 9 4 4

(r)

The procedure was carried out in a similar manner to that in Reference Example 4 (a), except that the addition was performed with 3-methoxy-4- (3-o-tolyl-ureido) -phenylacetic acid and ethyl (R / S) 3- (2,3-dihydro-1H-indol-5-yl) -pentanoic acid [see Reference Example 24 (b)], the product obtained was subjected to flash chromatography on silica gel, where as eluent dichloromethane / methanol (99: 1 by volume) to give (R / S) 3- (1 - {[3-methoxy-4- (3-o-tolyl-ureido) ethyl ester) 1-Phenyl] -acetyl} -2,3-dihydro-1H-indol-5-yl) -pentanoic acid.

(with)

The procedure was carried out in a similar manner to that in Reference Example 4 (a), except that in this case the addition was carried out with 4- (2,3-dihydro-1H-indole-1-carbonyl) acid. amino] -3-methoxy-phenylacetic acid and ethyl ester (Ø / W)

3- (2,3-dihydro-1H-indol-5-yl) -pentanoic acid [see Reference Example 24 (b)], to give (R / S) 3 - [- ({4 - [( 2,3-dihydro-1H-indole-1-carbonyl) -amino] -3-methoxy-phenyl} -acetyl) -2,3-dihydro-1H-indol-5-yl] -pentanoic acid as a white solid .

MS (ES ⁺ ) 578 (MNa &lt; ⁺ & gt ^; ).

(t)

The procedure of this embodiment was performed in a similar manner to that in Reference Example 4 (a), except that in this case the addition was performed

242 9 9 9 9 9 9

9 ^: 9 9 9 9 · 9 9

9 99 · 9 9 9 99 9 9 with 9-methoxy-4- (3-o-tolyl-ureido) -phenylacetic acid and ethyl (R / S) 3- (2,3-dihydro-1H-indol-5-yl) -3-phenyl-propionic acid [see Reference Example 24 (c)], the product obtained was subjected to flash chromatography on silica gel, eluting with a mixture of: pentane: ethyl acetate (1: 1 by volume) to give (R / S) 3- (1 - {[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -phenyl] - acetyl} -2,3-dihydro-1H-indol-5-yl) -3-phenyl-propionic acid as a foam.

• (u)

The procedure was carried out in a similar manner to that in Reference Example 4 (a), except that the addition was carried out with 4 - [(2,3-dihydro-1H-indole-1-carbonyl) acid in this case. (amino) -3-methoxy-phenylacetic acid and ethyl ester (R / S)

3- (2,3-dihydro-1H-indol-5-yl) -3-phenylpropionic acid [see Reference Example 24 (c),] to give (R / S) 3 - [- ({ 4 - [(2,3-dihydro-1H-indole-1-carbonyl) amino] -3-methoxyphenyl} acetyl) -2,3-dihydro-1H-indol-5-yl] -3-phenyl- propionic gray-white solid.

MS (ES ⁺ ) 626 (MNa &lt; ⁺ & gt ^; ).

Reference Example 5 (a) (R / S) 3- (2,3-Dihydro-1H-indol-5-yl) -butyric acid ethyl ester

A solution containing (R / S) (1-boc-2,3-dihydro-1H-indol-5-yl) -butyric acid ethyl ester (3.1 grams, Reference Example 6) was used.

243

0 00 • 00 0 0 0 • 0 0 0 0 0 0 '0 0 0 0 0 0 0 0 000 0 0 0 0 · 0 0 0 0 0 ·· ·· 0 0 0 00 0

in dichloromethane (30 mL), cooled in an ice bath, treated with trifluoroacetic acid (30 mL). after about 30 minutes, the reaction mixture was evaporated and traces of trifluoroacetic acid were removed by stripping off toluene (twice) to give the title compound as a dark viscous gum which was used immediately without further purification.

(b)

The procedure was carried out in a similar manner to that in Reference Example 4 (a), except that ethyl ester (R / S) was used.

3- (1-boc-1,2,3,4-tetrahydroquinolin-6-yl) -butyric acid (Reference Example 11), to give (R / S) 3- (1,2,3, 3-methyl-ethyl) ester. 4-tetrahydroquinolin-6-yl) -butyrate.

(C)

The procedure was carried out in a similar manner to that described in Reference Example 4 (a), except that (R / S) 4- (1-boc-1,2,3,4-tetrahydroquinolin-6-yl) was used. -tetrahydropyran-2-one- (Reference Example 16) and the reaction was carried out at room temperature to give (R / S) 4- (1,2,3,4-tetrahydroquinolin-6-yl) -tetrahydropyran-2- ob as a brown solid.

Reference Example 6

(R / S) 3- (1-Boc-2,3-dihydro-1H-indol-5-yl) butyric acid ethyl ester.

A mixture of ethyl 3- (1-boc-2,3-dihydro-1H-indol-5-yl) - 244 was used.

• ·· * · · · 9 99 9 '9 9 99 9 9. 0 • · • · ·· 9 · 9 9999 • · 9 • · 9 9 9 9 9 999 99 9 9 9 • 0 • 9

-rotrotone (11.4 grams, Reference Example 7) and ammonium formate (about 30 grams) in ethanol (about 200 milliliters), which was heated in an oil bath to 60 ° C. Palladium on charcoal (10%, about 1 gram) was then added as a one-shot addition under a nitrogen atmosphere, with sudden sudsing occurring. The mixture was then stirred at about 60 ° C for about one hour, then cooled to room temperature and filtered through Celite. The filtrate was evaporated and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water, then dried and then evaporated to give the title compound as a colorless moving oil.

Yield: 11.1 g. . .

Reference Example 7 (a) 3- (1-Boc-2,3-dihydro-1H-indol-5-yl) -crotonic acid ethyl ester

A mixture comprising 1-boc-5-bromoindoline (15,70 Hgram Reference Example 8), ethyl crotonate (8.6 g), palladium acetate (480 mg), tris (o tolyl) phosphine (1.6 g) and triethylamine (10 ml) in dimethylformamide (60 ml), wherein; the mixture was stirred, in a sealed vessel under argon, at a temperature of about 100 ° C for about 4 hours. After cooling to room temperature, the dark mass was poured into hydrochloric acid (about 1 liter, 1M solution) and the product obtained was extracted into ethyl acetate. The combined extracts were washed with aqueous sodium bicarbonate solution and then with brine, dried and evaporated. The residual light yellow oil was then

245

·· ·· * · ·> • »» ·· • • * • ···· ♦ »· • · · · • • • · «· • ·· » • •

subjected to flash chromatography on silica gel, eluting with ethyl acetate / gasoline (5: 95 by volume) to remove highly volatile impurities and then with ethyl acetate / gasoline (1: 9 by volume) to give the title compound as a colorless mobile oil.

Yield: 11.4 g.

(b)

The procedure was similar to that in Reference Example 7 (a), except that methyl acrylate was used and the reaction was carried out at 80 ° C to give 3- (1-boc) methyl ester. -2,3-dihydro-1H-indol-5-yl) -acrylic acid as a light yellow solid.

MS (ES ⁺ ) 629 (2 M Na ⁺ ).

(C)

The procedure of this embodiment was carried out in a similar manner to that of Reference Example 7 (a) except that -1-boc-6-iodo-1,2,3-tetrahydroquinoline (see Reference Example 12) was used and 3- (1-Boc-1,2,3,4-tetrahydroquinolin-6-yl) -crotonic acid ethyl ester was prepared as a pale yellow solid.

(d)

The procedure of this embodiment was carried out in a similar manner to that in Reference Example 7 (a) except that 1-boc-6-iodo-1,2,3,4-tetrahydroquinoline was used (see Reference Example 12), and methyl acrylate and the reaction was carried out at 80 ° C,

• · ·

- 246

9 9 »9»

the methyl ester was prepared

3- (1-boc-1,2,3,4-tetrahydroquinolin-6-yl) -acrylic acid as a pale yellow powder.

Reference Example 8

1-Boc-5-bromoindoline.

5-bromoindoline (10 grams) was added as a one-time addition to molten boc-anhydride (11.6 grams) at a temperature ranging from 30 to 40 ° C. Immediately after foaming, a solid cake began to form, which was triturated with pentane to give the title compound as a white powder.

Yield: 15 g.

Reference Example 9 (a) 2- (2,3-Dihydro-1H-indol-5-ylmethyl) pentanedioic acid dimethyl ester.

A mixture comprising 3- (1-boc-2,3-trihydropyr-1H-indol-5-yl) -2-methoxycarbonylpentanedioic acid dimethyl ester [530 mg, Reference Example 10 (a)] and concentrated acid was used. hydrochloric acid (20 ml) was stirred at reflux overnight and then evaporated. The residual clean foam (370 mg) was then treated with methanol (20 mL) followed by concentrated sulfuric acid (10 drops). The resulting solution was then stirred at reflux for 2 hours and then evaporated. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution, the layers separated and the aqueous layer was separated

··

247 extracted with ethyl acetate. The organic layer and extracts were combined and washed with brine then dried and evaporated. The residue was flash chromatographed on silica gel, eluting with ethyl acetate / petrol (1: 1, v / v) to give the title compound as a clear oil.

Yield: 150 mg.

MS (ES ^&lt; ^{+ &gt;} ) 278 (MH ^&lt; ^{+ &gt;} ).

(b)

The procedure was carried out in a similar manner to that in Reference Example 9 (a), except that 3- (1-boc-1,2,3,4-tetrahydroquinolin-6-yl) - ethyl ester was used. 2-ethoxycarbonyl-pentadiate [see Reference Example 10 (b)] to give 3- (1,2,3,4-tetrahydroquinolin-6-yl) -pentadiic acid dimethyl ester as a colorless oil.

MS (ES ⁺ ) 292 (MH &lt; ⁺ &gt;), 314 (MNa &lt; ⁺ & gt ^; ).

and

Reference Example 10 ----------- --------------------, _ i____ ____________ (a) 3- (1-Boc-2) dimethyl ester, 3-Dihydro-1H-indol-5-yl) -methoxycarbonyl-pentanedioic acid.

. A stirred solution containing sodium (156 milligrams) in methanol (15 ml) was treated with dimethyl malonate (0.8 ml), and after stirring for 15 minutes, the reaction mixture was treated with a methyl ester solution. 3- (1-boc-2,3-dihydro-1H-indol-5-yl) -acrylic acid [1.0 gram, see Reference Example 7 (b)]

- 248 ft ft 9 ft ft ft ft -4 -4 ^^ - 4 ft s · · · · ····· Ftft. Ftft. In tetrahydrofuran (15 mL). The reaction mixture was stirred at reflux for 3 hours, cooled to room temperature and treated with water (2 mL) and then evaporated. The residue was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with fresh ethyl acetate. The organic layer and extracts were combined and washed with brine then dried and evaporated. The residue was flash chromatographed on silica gel, eluting with ethyl acetate / petrol (15: 85, v / v) to give the title compound as a clear oil.

Yield: 530 mg.

MS (ES ⁺ ) 458 (MNa &lt; ⁺ & gt ^; ).

MS (ES &lt; ^{- &gt;} ) 434 (M).

(b)

The procedure of this embodiment was carried out in a similar manner to the procedure described above. of Reference Example 10 (a), except that 3- (1-boc-1,2,3,4-tetrahydroquinolin-6-yl) -acrylic acid methyl ester was used [see Reference Example 7 (d)] and 3- (1-boc-1,2,3,4-tetrahydroquinolin-6-yl) -2-ethoxycarbonylpentanedioic acid ethyl ester was thus obtained.

MS (ES ⁺ ) 514 (MNa &lt; ⁺ & gt ^; ).

MS (ES) 490 (M +).

Reference Example 11 (a) (R / S) 3- (1-Boc-1,2,3,4-tetrahydro-quinolin-6-yl) -butyric acid ethyl ester.

·· ··> 0, 0 '0 0 0 0 0 9 • / 9 9 «<· · · ·

99 p ·. · 999 9th, 9 0 ·

9 9 -.9 ´ «· · ·· ·· · 0 · ·

A mixture comprising 3- (1-boc-1,2,3,4-tetrahydroquinolin-6-yl) -crotonic acid ethyl ester [9 grams, see Reference Example 7 (c)] and 5% palladium was used. on charcoal (2.5 g) in ethanol (250 ml) and the mixture was hydrogenated at room temperature and pressure overnight. The spent catalyst was removed by filtration through Celite and the filtrate was evaporated to give the title compound as a colorless oil.

Yield: 9.1 g.

-Ϊ -. t (b). '. , '. , '· ‘

The procedure was carried out in a similar manner to that described in Reference Example 11 (a), except that E and Z of (R / S) 3- (1-acetyl-2,3-dihydro-1H) -ethyl ester were used. -indol-5-yl) -hept-2-enoic acid [see Reference Example 26 (b)], and hydrogenation was carried out at 100 psi of hydrogen for 100 minutes to prepare the ethyl ester ( R / S)

3- (1-acetyl-2,3-dihydro-1H-indol-5-yl) -heptanoic acid as a white solid.

(C)

The procedure was carried out in a similar manner to that in Reference Example 11 (a), except that E and Z of ethyl (R / S) 3- (1-acetyl-2,3-dihydro-1H) were used. (indol-5-yl) -pent-2-ene [see Reference Example 26 (b)] and hydrogenation was carried out at 100 psi (2 bar) of hydrogen for 100 minutes, thereby

ethyl acetate (R / S) was prepared

3- (1-acetyl-2,3-dihydro-1H-indol-5-yl) -pentanoic acid as a white solid.

- 250 -

• 00 ·· 0 • 0 '00 .0 1 · · · t · .. , «· · • 0 0 0 0 · 0000 00> 0 · : · · · ». · · .0 •. · 0 00 91 ·· • • 0 0

(d)

The procedure was carried out in a similar manner to that in Reference Example 11 (a), except that E and Z ethyl (R / S) of 3- (1-acetyl-2,3-dihydro-1H) were used. -indol-5-yl) cinnamic acid [see Reference Example 26 (c)] and hydrogenation was carried out at 2 bar of hydrogen for 120 minutes to prepare ethyl ester (R / S).

3- (1-Acetyl-2,3-dihydro-1H-indol-5-yl) -3-phenyl-propionic acid as a white solid.

Reference Example 12 1-Boc-6-iodo-1,2,3,4-tetrahydroquinoline.

A solution of iodine chloride (16.2 grams) in acetic acid (30 mL) was added to the stirred solution.

1,2,3,4-tetrahydroquinoline (12.6 milliliters)) in acetic acid (125 milliliters) at a temperature of

----- room under nitrogen atmosphere. After stirring at room temperature for an additional hour, the dark colored mixture was poured into water (about 500 mL) and the reaction mixture was basified by careful addition of solid potassium carbonate. The aqueous layer was extracted with tert-butyl methyl ether, and the extract was washed successively with aqueous sodium thiosulfate solution and then brine, dried and then evaporated. The resulting brown gum (22 grams) was then treated with boc-anhydride (44 grams) in tetrahydrofuran (250 mL). The mixture was stirred at reflux temperature, evaporated, and the residue partitioned between ethyl acetate and

251. ·: ·· ·· · ·· '·· -. · I * · 9 9 · ·. · · · · · · ·

dilute hydrochloric acid solution. The organic layer was washed with brine, dried, and then evaporated. Crystallization of the residue from heptane gave the title compound as a pale yellow powder.

Yield: 15 g.

Reference Example 13 (a) (R) 4- [1- (1,2,3,4-Tetrahydro-quinolin-6-yl) -2-methoxycarbonyl-ethylcarbamoyl] -butyric acid methyl ester.

A stirred solution containing (R) 3-amino-3- (1-boc-1,2,3,4-tetrahydroquinolin-6-yl) -propionic acid methyl ester (1.7 grams, Reference Example 14) was used. in tetrahydrofuran (50 mL) which was treated with glutaric anhydride. After stirring for 4 hours, the mixture was evaporated to dryness and the residue was dissolved in methanol (40 ml) and treated with concentrated sulfuric acid (20 drops). The solution was stirred at reflux for 3 hours and then allowed to stand at room temperature overnight. After addition of solid sodium bicarbonate (10 grams), the mixture was evaporated to dryness and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate. The aqueous layer was extracted with fresh ethyl acetate. The organic layer was combined with the extracts and washed with brine then dried and then evaporated. The residue was subjected to flash chromatography on silica gel, eluting with hexane

252 and using the above procedure, the title compound as yellow acetate was used in ethyl acetate to give the desired oils.

Yield: 1.6 g.

MS (ES ⁺ ) 363 (MH &lt; ⁺ &gt;), 385 (MNa &lt; ⁺ & gt ^; )

MS (ES) 361 (MH +).

(b)

In a similar manner to the procedure in Reference Example 13 (a), except that succinic anhydride was used, acid poloamide (R) was prepared.

N- [2-methoxycarbonyl-1- (1,2,3,4-tetrahydroquinolin-6-yl) -ethyl] -succinate as a colorless oil.

MS (ES &lt; ⁺ & gt ^; ) 371 (MNa &lt; ⁺ & gt ^; )

Reference Example 14>

(R) 3-Amino-3- (1-boc-1,2,3,4-tetrahydroquinolin-6-yl) -propionic acid methyl ester.

A solution containing 3- {R} - [benzyl - ({S} -1-phenylethyl) -amino] -3- (1-boc-1,2,3,4-tetrahydroquinoline-6-) methyl ester was used. 1-propionic acid (6.5 grams, see Reference Example 15) in ethanol (100 milliliters) which was treated with 20% palladium hydroxide on activated carbon (1.0 grams), acetic acid (3.6 milliliters) and water (10 mL) and the mixture was then hydrogenated at room temperature overnight. The spent catalyst was then removed by filtration through Celite and the filtrate was evaporated to a small volume. The residue was then taken up in ether and the solution was washed with aqueous sodium bicarbonate and the layers separated. The aqueous layer was extracted twice with fresh ether and the ether extracts were combined

- 253 ι:

And the combined fraction was washed with brine, dried and then evaporated. The residue was flash chromatographed on silica gel, eluting with methanol: dichloromethane (1: 9, v / v) to give the title compound as a clear oil which slowly crystallized on standing.

Yield: 1.7 g.

MS (ES ⁺ ) 335 (MH &lt; ⁺ &gt;), 357 (MNa &lt; ⁺ & gt ^; ), 669 (2MH ^& lt ^{; +} & gt ^; ).

Reference Example 15

3- {R} - [Benzyl - ({S} -1-phenylethyl) -amino] -3- (1-boc-1,2,3,4-tetrahydroquinolin-6-yl) -propionic acid methyl ester

A solution containing (S) -N-benzyl-α-methylbenzylamine (2.6 mL) in anhydrous tetrahydrofuran (50 mL) was cooled to -70 ° C under a nitrogen atmosphere. solution of butyllithium in hexanes (5 ml, 2.5 M solution) by adding this solution of butyllithium dropwise until a red solution was obtained. After stirring the reaction mixture at -70 ° C for an additional 40 minutes, the reaction mixture was worked up by dropwise addition of a solution of 3- (1-boc-1,2,3,4-tetrahydroquinoline) methyl ester. 6-yl) -acrylic acid [2.0 grams, Reference Example 7 (d)] in tetrahydrofuran (20 mL) over 10 minutes. Stirring was then continued at low temperature for an additional 20 minutes and then allowed to warm to room temperature. The mixture was partitioned between ether and water and the layers separated

254 · 4 · 4 · 4 4444 44 4

The organic layer was then washed with water and then brine and finally dried and then evaporated. The residue was flash chromatographed on silica gel, eluting with ethyl acetate / petrol (1: 9, then 15: 85, v / v) to give the title compound as a viscous colorless oil. E.

Yield: 1.5 g.

Reference Example 16 (R / S) 4- (1-boc-1,2,3,4-tetrahydroquinolin-6-yl) -tetrahydro-pyran-2-one.

A mixture containing 1-boc-6-iodo-1,2,3,4-tetrahydroquinoline (2.0 grams, Reference Example 12), 5,6-dihydropyran-2-one (1,1 tetrakis (triphenylphosphine) palladium and triethylamine (2.2 g) in dimethylformamide (5 ml) were stirred at about 95 ° C in a sealed vessel under nitrogen overnight. The reaction mixture was then partitioned between ^- * ethyl acetate and a dilute acid solution chlorovodíkové.jednotlivé layers were separated, the organic layer was washed with sodium bicarbonate solution, then dried and then evaporated. The residue was subjected to flash chromatography on silica gel, eluting with ethyl acetate / cyclohexane (2: 3 by volume) to give the title compound as a brown oil.

Yield: 1.2 g.

- 255 • 9 9 9 9 9 99 9 9 9 9 9 9 9 9 9

999 9 9 9 9999

9 9 9 9 9 9 9 • 99 99 99 99 99 999

Reference Example 17

(R) (1-Boc-1,2,3,4-tetrahydroquinolin-6-yl) -3 - [(5-methylisoxazole-3-carbonyl) -amino] -propionic acid methyl ester.

A solution containing 5-methylisoxazole-3-carboxylic acid (65 mg) in dimethylformamide (30 mL) was treated successively with O- (7-azabenzotriazol-1-yl)-yl, Ν, Ν ', N 1'-tetramethyluronium hexafluorophosphate (190 milligrams), diisopropylethylamine (1 ml) and (R) 3-amino-3- (1-boc-1,2,3,4-tetrahydroquinolin-6-yl) propionic acid methyl ester (200 milligrams) , Reference Example 14). The reaction mixture was allowed to stand at room temperature overnight, then evaporated to a small volume and the residue partitioned between ethyl acetate and dilute hydrochloric acid. The layers were separated and the organic layer was washed with sodium carbonate solution, dried and evaporated, the residue purified by flash chromatography to give the title compound as an orange gum ______; _________________ ________

Yield: 310 mg.

Reference Example 18

(S) 2-Amino-3- [1- (2,6-dichloro-benzoyl) -1,2,3,4-tetrahydro-quinolin-6-yl] -propionic acid methyl ester.

A solution containing (S) 2- (N-boc-amino) -3- (1,2,3,4-tetrahydroquinolin-6-yl) -propionic acid methyl ester [500 milligrams, Reference Example 19 (a) was used. ]] in tetrahydrofuran (20 ml) was treated successively with triethylamine (360 mg) and 2,6-dichlorobenzoyl chloride (380 ml).

256

milligrams). The reaction mixture was stirred at 40 ° C for 2 hours, then partitioned between ethyl acetate (100 mL) and dilute hydrochloric acid (100 mL). The organic phase was washed with sodium bicarbonate solution, dried and evaporated. The residue was dissolved in trifluoroacetic acid (2 mL) and the clear solution was allowed to stand at room temperature for 30 minutes, then evaporated. The residue was partitioned between ethyl acetate and dilute hydrochloric acid solution. The organic phase was washed with sodium bicarbonate solution, dried and evaporated to give the title compound as a colorless oil.

Yield: 200 mg.

Reference Example 19 (a) (S) 2- (N-Boc-amino) -3- (1,2,3,4-tetrahydroquinolin-6-yl) -propionic acid methyl ester.

A solution containing (S) 2- (N-boc-amino) -3-quinolin-6-yl-propionic acid methyl ester [3.8 g, Reference Example 20 (a)] in ethanol (100 ml) was used. ), which was treated at 60 ° C with ammonium formate (10 grams) and 10% palladium on charcoal (500 milligrams). After stirring the mixture at 60 ° C, an additional amount of ammonium formate (about 5 grams) and palladium on charcoal (about 250 milligrams) was added, and this treatment was repeated at 30 minute intervals for a further 2 hours at which time TLC analysis (thin layer chromatography) indicated that the reaction was complete. After cooling to room temperature, this was

- 257 • 8 *

9 t ··

9 · · · · · ·

9 9 9 · 9999

9 9 9

The mixture was filtered through Celite to remove the spent catalyst and the filtrate was evaporated. The residue was partitioned between ethyl acetate (200 mL) and sodium bicarbonate solution (200 mL). The organic phase was dried and evaporated to give the title compound as a colorless oil, which crystallized slowly on standing.

Yield: 3.8 g.

(b)

In a similar manner to that described in Example 49 (a) except that (S) 2-acetylamino-3- (1,2,3,4-tetrahydroquinolin-6-yl-propionic acid methyl ester) was used. [Reference Example 20 (b)] and carrying out the reaction at reflux temperature for 2 hours, the methyl ester of the acid (S) was prepared.

2-acetylamino-3-quinolin-6-yl) -propionic acid as a colorless oil.

MS (ES ⁺ ) 277 (MH &lt; ⁺ &gt;), 299 (MNa &lt; ⁺ & gt ^; )

Reference Example 20 (a) (S) 2- (N-Boc-amino) -3-quinolin-6-yl-propionic acid methyl ester.

In this example, a blend containing a blend was used. (S) 2-Amino-3-quinolin-6-yl-propionic acid methyl ester (3.0 grams, Reference Example 21) and boc-anhydride (3.2 grams) in tetrahydrofuran (30 mL), The mixture was stirred at reflux for 30 minutes. The reaction mixture was evaporated and the residue was triturated with pentane to give the title compound as a white powder.

- 258

S. · · · í · «9 44 44 44 44 44 44 44 44

9 9 49 i »4

Yield: 3.8 g.

(b)

In a similar manner to that described in Example 49 (a), except that acetic anhydride was used, the methyl ester (S) was prepared.

2- (acetylamino) -3-quinolin-6-yl-propionic acid as a colorless oil which slowly crystallized on standing.

MS (ES ⁺ ) 273 (MH ^&lt; ^{+ &gt;} ), MS (ES) 271 (M &lt; - &gt;).

Reference Example 21

(S) 2-Amino-3-quinolin-6-yl-propionic acid methyl ester.

A solution containing butyllithium in hexanes (13.4 ml, 2.5 M solution) was added dropwise to the solution containing (R).

2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (5.2 g) in anhydrous tetrahydrofuran (80 mL) at -78 ° C under nitrogen. After stirring at -78 ° C for 10 minutes, the solution was treated with a solution of 6- (6-chloromethyl) -quinoline [5.0 grams, prepared according to the procedure of: Mahiou, Belaid; Gleicher, Gerald Jay. J. Org. Chem. (1990), 55 (14), 4466-9} in tetrahydrofuran (20 mL). The resulting dark orange-colored reaction mixture was then stirred at -78 ° C for 2 hours. The cold reaction mixture was then poured into a mixture of ethyl acetate (200 mL) and brine (200 mL). The organic phase was then dried and evaporated. The residue was subjected to flash chromatography on silica gel, eluting with ethyl acetate: dichloromethane (1: 1, v / v) to give a colorless oil (6 grams). This substance • 4 ♦

- 259 £ ·· • 4 4

* · * · • ··· ♦

It was then treated with hydrochloric acid (250 ml, 0.25 M solution) and the resulting solution was allowed to stand at room temperature for one hour and then evaporated. The residue was treated with water (30 mL) and basified by the addition of concentrated ammonia (50 mL). The reaction mixture was extracted three times with dichloromethane (100 mL). The combined extracts were dried and evaporated. The residue was flash chromatographed on silica gel, eluting with ethyl acetate to remove volatile impurities followed by methanol / ethyl acetate (1: 1, v / v) to give the title compound as a colorless gum. substances.

Yield: 3.0 g.

Reference Example 22

(1-Boc-2-o-tolylamino-1H-benzimidazol-5-yl) -acetic acid.

- (2-o-Tolylamino-1H-benzimidazol-5-yl) -acetic acid ethyl ester (R / S) (1.6 g, Reference Example 23) was suspended in ethanol (30 ml) ) and this solution was treated with sodium hydroxide solution (5 mL, 1 M solution). after stirring the solution at 40 ° C for 2 hours, the mixture was evaporated. The residue was partitioned between dilute acetic acid (50 mL) and dichloromethane (50 mL) and the resulting white precipitate (650 mg) was dissolved in acetonitrile (30 mL) and this solution was then treated with boc-anhydride (580 mg) and dimethylaminopyridine (50 mL). 10 milligrams). The reaction mixture was then allowed to stand at room temperature

♦ 9

- 260 * 9 9 · 9. 9 * 9 9 9

99999 * 9

The mixture was concentrated at room temperature overnight, evaporated and the residue partitioned between ethyl acetate and dilute acetic acid. The organic layer was then dried and then evaporated. The residue was dissolved in methanol (2 mL) and this solution was then treated with ether. The resulting precipitate was collected by filtration to give the title compound as a white powder.

Yield: 500 mg.

Reference Example 23

(R / S) (2-O-Tolylamino-1H-benzoimidazol-5-yl) -acetic acid ethyl ester.

A solution of (3,4-diaminophenyl) acetic acid ethyl ester (4.1 grams) in ethanol (50 mL) was treated with o-tolyl isothiocyanate (3.1 grams). The reaction mixture was then allowed to stand at room temperature overnight and the clear solution was evaporated to give a yellow gum which was treated with ethanol (70 mL). The resulting solution was then treated with diisopropylcarbodiimide (5.3 g) and the mixture was stirred at 55 ° C for 4 hours and then evaporated. The residue was flash chromatographed on silica gel, eluting first with ether and then with a 1: 9 mixture of methanol and ether to give the title compound as a pale yellow gum.

Yield: 4.1 g.

261 ftft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ·· ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft

Reference Example 24 (a) (R / S) 3- (2,3-Dihydro-1H-indol-5-yl) -heptanoic acid ethyl ester.

A solution containing (R / S) 3- (2,3-dihydro-1H-indol-5-yl) -heptanoic acid hydrochloride [4.13 grams, Reference Example 25 (a)] in absolute ethanol was used. 100 ml) containing concentrated sulfuric acid (1.4 ml), the solution was stirred for 6 hours and then allowed to stand overnight at room temperature. The reaction mixture was concentrated to a small volume and the residue was partitioned between ethyl acetate (200 mL) and saturated aqueous sodium bicarbonate solution (200 mL). The organic phase was then washed with a saturated aqueous solution of sodium bicarbonate (50 mL). The aqueous phases were further extracted with ethyl acetate, the organic phases were combined, dried over magnesium sulfate and evaporated. The residue was flash chromatographed on silica gel, eluting with pentane / ethyl acetate (2: 1, v / v) to give the title compound as a pale yellow oil.

Yield: 2.88 g.

(b)

In a similar manner to Reference Example 24 (a) except that (R / S) 3- (2,3-dihydro-1H-indol-5-yl) -pentanoic acid hydrochloride was used [see Reference Example 25 (b)] was prepared (R / S) ethyl ester according to this embodiment

262

to · - ·  ·· • * • • it to to '· • it • • · · • · to · • · · · • · it * · It • • - · • to ' · »» •

3- (2,3-Dihydro-1H-indol-5-yl) -pentanoic acid as a pale yellow oil. , ‘(C)

In a similar manner to that described in Reference Example 24 (a), except that (R / S) 3- (2,3-dihydro-1H-indol-5-yl) -3-phenyl- propionic acid [see Reference Example 25 (c)] was prepared (R / S) ethyl ester according to this embodiment

3- (2,3-dihydro-1H-indol-5-yl) -3-phenylpropionic acid as a light orange oil.

Reference Example 25 (a) (R / S) 3- (2,3-Dihydro-1H-indol-5-yl) -heptanoic acid hydrochloride

A suspension of (R / S) 3- (1-acetyl-2,3-dihydro-1H-indol-5-yl) -heptanoic acid ethyl ester [3.95 g, Reference Example 11 (b)] was used, in an aqueous solution of hydrochloric acid (120 mL, 6 M solution), which was heated at 85 ° C for 7 hours. After cooling to room temperature, the mixture was evaporated. The residue was treated with toluene and the solvent was evaporated under reduced pressure (repeated two more times). After final drying in a desiccator, the title compound was obtained as an orange-brown oil.

Yield: 4.13 g.

LC-MS: R y = 3.36 minutes;

MS (ES ^&lt; ^{+ &gt;} ) 248 (MH ^&lt; ^{+ &gt;} ).

263 9 9 9999 9999 9999 9999 9999 9999 9999 9999 9999 9999 9999 9999

9 99 9 9 '9' 9 9 9 99

In a similar manner to that described in Reference Example 25 (a), except that (R / S) 3- (1-acetyl-2,3-dihydro-1H-indol-5-yl) - of pentanoic acid [see Reference Example 11 (c)], the acid hydrochloride (R / S) was prepared

3- (2,3-dihydro-1H-indol-5-yl) -pentanoic acid as a brown oil e.

(C)

In a similar manner to that described in Reference Example 25 (a), except that (R / S) 3- (1-acetyl-2,3-dihydro-1H-indol-5-yl) - 3-Phenyl-propionic acid [see Reference Example 11 (d)] was prepared (R / S) 3- (2,3-dihydro-1H-indol-5-yl) -3-phenylpropionic acid hydrochloride as brown solids.

Reference Example 26 (a) 3- (1-Acetyl-2,3-dihydro-1H-indol-5-yl) -hept-2-enoic acid ethyl ester of E and Z.

Sodium hydride (1.09 grams, 60% dispersion in mineral oil) was suspended in tetrahydrofuran (150 mL). The mixture was cooled in an ice bath under nitrogen and triethylphosphonacetate (4.75 ml) was added over 3 minutes. After 45 minutes, a solution containing

1-acetyl-5-pentanoyl-2,3-dihydro-1H-indole [5.33 g, Reference Example 27 (a)] in tetrahydrofuran (50 mL) was added dropwise at 50 minute intervals. After stirring for 15 minutes

264 The resulting reaction mixture was allowed to warm to room temperature and was then allowed to warm to room temperature. heated on a steam bath for 20 hours under a nitrogen atmosphere. Sodium hydride (1.09 g, 60% dispersion in mineral oil) in tetrahydrofuran (150 mL) was suspended in a separate vessel. The reaction mixture was cooled in an ice bath under nitrogen, triethylphosphonacetate (4.75 ml) was added over 3 minutes, and the reaction mixture was stirred for 70 minutes. The reaction mixture was then added via cannula to the bulk of the reaction mixture while cooling in an ice bath. The reaction mixture was heated to reflux for 43 hours, cooled, then concentrated to half volume and finally partitioned between ethyl acetate and 0.33 M aqueous hydrochloric acid. the organic phase was separated and the aqueous phase was re-extracted with ethyl acetate. The combined organics were dried over magnesium sulphate and evaporated to give an orange-brown oil which was flash chromatographed on silica gel using ethyl acetate / pentane (1: 1 v / v) as eluent. ) to give the title compound. Yield: 4.3 g.

(b)

In a similar manner to that described in Reference Example 26 (a), except that it was used

1-Acetyl-5-propanoyl-2,3-dihydro-1H-indole [see Reference Example 27 (b)], ethyl E and Z 3- (1-acetyl-2,3-dihydro- 1H-Indol-5-yl) -pent-2-ene as a cream solid.

265

·· »· · 1 • 99 • 9 9 9 99 »· 8 · 9999 99 '· »· 9 9 9! '9 • · • 9 ♦ · ·· ·

(C)

In a similar manner to that described in Reference Example 26 (a), except that it was used

1-acetyl-5-benzoyl-2,3-dihydro-1H-indole [see Reference Example 27 (c)], ethyl E and Z 3- (1-acetyl-2,3-dihydro- 1H-indol-5-yl) cinnamon as a yellow solid.

Reference Example 27 (a) 1-Acetyl-5-pentanoyl-2,3-dihydro-1H-indole.

Pentanoyl chloride (10.8 grams) was added dropwise to a mixture of anhydrous aluminum chloride (28.2 grams) and 1-acetyl-2,3-dihydro-1H-indole (10 grams) in 1,2-dichloroethane ( 100 ml) with mechanical stirring. The reaction mixture was stirred at reflux for 16 hours, cooled and then poured into ice-water. The resulting mixture was extracted with dichloromethane. The extracts were washed with 1 M aqueous sodium hydroxide solution, dried over magnesium sulfate and then evaporated to give the title compound as a dark gum.

Yield: 10.3 g.

(b)

In a similar manner to Reference Example 27 (a), except that propionyl chloride was used and the product was subjected to flash chromatography on silica gel, eluting with a mixture of ethyl acetate and pentane (3: 3, v / v): 2) was ready

266 -

• · · • · 4 4 4 • - · 4 4 4 4 • · · · 4 4444 4 · · · • · 4 4 9 • · · ··· · ♦ 9 4 ‘ 4 9 · ·

1-acetyl-5-propanoyl-2,3-dihydro-1H-indole as a cream-orange solid.

(C)

In a similar manner to Reference Example 27 (a) except that benzoyl chloride was used and the product was subjected to flash chromatography on silica gel, eluting with a mixture of ethyl acetate and pentane (3: 3 by volume): 2) 1-acetyl-5-benzoyl-2,3-dihydro-1H-indole was prepared as a cream solid.

Reference Example 28

(R / S) 6- (2-Carboxy-1-methylethyl) -3,4-dihydro-2H-quinoline-1-carboxylic acid 9H-fluoro-9-ylmethyl ester.

A suspension of (R / S) 3- (1,2,3,4-tetrahydroquinolin-6-yl) -butyric acid (2.6 grams) and sodium bicarbonate (2.2 grams) in acetone (40 g) was used. ml) and water (40 ml) which was treated with 9H-fluoren-9-ylmethyl ester

2,5-dioxopyrrolidine-1-carboxylic acid (4.0 grams) and the resulting reaction mixture was then stirred at room temperature overnight. The mixture was then filtered and the filtrate was evaporated to a small volume. The residue was then treated with dilute aqueous hydrochloric acid to give a gummy precipitate which was extracted into a mixture of tetrahydrofuran, ethyl acetate and dichloromethane. The solution was washed with brine, dried and then evaporated to give the title compound as a pale brown oil which solidified on standing.

H · ε

- 267 -

• ·· ·· • · · 00 • • 0 00 0 0 · 00 00 · · 0 0 00 0 0 0 0 • 0 0 0 0 0 -0 • 000 0 0 • 00 9

ECACC-dependent adhesion, Porton

Yield: 5.8 g.

MS (ES ⁺⁾ 464 (MNa ^+), MS (ES ^-) 440 (M ^-).

In vitro and in vivo tests

1. Inhibitory effects of compounds on cellular

VLA4 to fibronectin and VCAM

1.1 Metabolic labeling of RAMOS cells

RAMOS cells (pre-B cell line,

Down, UK) are grown in RPMI culture medium (Gibco,

UK) supplemented with 5% fetal calf serum (FCS, Gibco, UK). Prior to the assay, cells are resuspended at a concentration of 0.5 x 10 6 cells / ml RPMI and labeled with 400 μΩί / ΙΟΟ ml [ ³ H] -methionine (Amersham, UK) for 18 hours at 37 ° C.

1.2 Preparation of 96-well Adhesion Assay Plates __ Cytostar plates (Amersham, UK) were coated with μΐ / well of either 3 μg / ml human soluble VCAM-1 (R&D Systems Ltd., UK) or 28.8 μg / Inl human tissue fibronectirium ( Sigma, UK). 50 μΐ of phosphate buffered saline was added to the non-specific binding control wells. The plates were then dried in an incubator at 25 ° C overnight. The next day, the plates were blocked with 200 μΐ / well of Pucks buffer (Gibco, UK) supplemented with 1% BSA (Sigma, UK). Plates were left in the dark at room temperature for 2 hours. The blocking buffer was then removed and the plates dried by inverting and gently tapping the paper. 50 μΐ / well was added to the appropriate binding assay wells and non-specific binding wells to the plate. * * ««··

268

3.6% dimethylsulfoxide in Pucks buffer supplemented with 5 mM manganese chloride (for integrin receptor activation, Sigma, UK) and 0.2% BSA (Sigma, UK). 50 μΐ / well of test compounds at the appropriate concentrations diluted with 3.6% dimethylsulfoxide in Pucks buffer supplemented with 5 mM manganese chloride and 0.2% BSA was added to the test wells.

Metabolically labeled cells were suspended at 4 x 10 6 cells / ml in Pucks buffer supplemented with manganese chloride and BSA as above. 50 μΙ / well of cells in 3.6% dimethylsulfoxide in supplemented Pucks buffer was added to all wells on the plate.

For VCAM-1 or fibronectin coated plates, the same procedure existed and it was examined how the compound inhibited cell binding to both substrates.

1.3 Test performance and data analysis

Plates containing! cells in control or test compound wells were incubated for 1 hour in the dark at room temperature.

Plates were then read on a Vallac Microbeta scintillation counter (Vallac, UK) and the data was processed by Microsoft Excel (Microsoft, US). Data were expressed as IC 50, the inhibitor concentration at which 50% binding occurred in the control samples. The percentage of bonds was determined from the equation:

{[(Utb ^- Cnc) ^- ( ^c i ^-c ns ^ / (Ctb ^- Cns)} ^x ιθθ ~% ^binding V

269 • 9 9 99 9 ·· ·, · · · · · · · · · · · · · · · · · · · · · ·

9 '99' 9 '9 9999' '· 9 · 9 9' * '9' 99 '9' 99 'in which:

Cjb are pulses bound to wells coated with fibronectin (or VCAM-1) without the presence of inhibitor,

Cjqs are pulses occurring in wells without substrate, and

C 1 are pulses from wells containing a cell adhesion inhibitor.

Data for the compounds of the present invention are expressed in the form of IC 50 by inhibiting cell adhesion to fibronectin and VCAM-1. Particular compounds of the invention inhibit cell adhesion to fibronectin and VCAM-1 with an IC 50 in the range of 100 gmol to 0.1 nniol. Preferred compounds of the invention inhibit cell adhesion to VCAM-1 fibronektinu.a IC _5Q within the range 10 nanomolar to 0.1 nanomolar.

2. Inhibition of antigen-induced airway inflammation in mice and rat

2.1. Sensitization of animals'

Rats (Brown Wellway, Olac, UK) were sensitized on days 0, 12 and 21 with Ovalbumin (100 gg, intraperitoneally, (i.p.), Sigma, UK) administered with aluminum hydroxide adjuvant (100 mg, i.p., Sigma,

In saline (1 ml, i.p.).

In addition, mice (C57) were sensitized on days 0 and 12 with ovalbumin (10 µg, i.p.) administered with aluminum hydroxide adjuvant (20 mg, i.p.) in saline (0.2 ml, i.p.).

• ·· • - · • ft ft · • • -ftft  · · '« • · · · Ft ftftftft • ft · • ft • · • • · • · · · • ft ' •

2.2

Rats were stimulated any day between 28th to 30th

On day 38, while mice were stimulated any day between days 20-30.

The animals were stimulated by exposure to 30 minutes (rats) or 1 hour (mice) of an ovalbumin aerosol (10 g / L) generated by an ultrasonic nebulizer (deVilbiss Ultraneb, US) and injected into the exposure chamber.

2.3 Care protocols

Animals were treated as needed before or after the antigen challenge. The water-soluble compounds of the present invention may be formulated in water (for oral, p.o., dosing) or saline (for intratracheal, i.t., administration). Insoluble compounds were prepared as suspensions by grinding and sonicating the solid in 0.5% methylcellulose / 0.2% polysorbate 80 in water (for p.o. administration, both Merck UK).

Ltd., UK) or in saline (for i.v. administration). Dose volumes were: for rats 1 ml / kg, p.o. or 0.5 ml / kg i.t., for mice 10 ml / kg, p.o. or 1 ml / kg, i.t.

2.4 Determination of airway inflammation

Cell accumulation in the lung was determined 24 hours post challenge (rat) or 48-72 hours post challenge (mice).

Animals were euthanized with sodium pentobarbital (200 mg / kg, i.p., Pasteur Merieux, France) and the cannula was immediately inserted into the trachea. Cells were removed from the airway lumen by bronchoalveolar lavage (BAL) and pulmonary

271

•, «4 · 4 4 4 4 4 4 44 4, '4 4 4 • ki 4 4 4 4? φ 44 44 4 4 4 4 · 4 '4 4 4444 4 4 4 4 - 4 4 4 4 4 4 4

enzyme tissue (collagenase, Sigma, UK) by digestion as described below.

BAL was performed by rinsing the airways with 2 aliquots (10 ml / kg each) of RPMI 1640 medium (Gibco, UK) containing 10% fetal calf serum (FCS, Serotec Ltd.,

UK). The obtained BAL aliquots were pooled and cells were counted as described below.

Immediately after BAL, pulmonary vascular supply was flushed with RPMI 1640 / FCS to remove blood cells. The lung lobes were excised and cut into 0.5 mm pieces. * Samples (rats: 400 mg, mice: 150 mg) of homogenous lung tissue were incubated in RPMI 1640 / FCS with collagenase (20 U / ml for 2 hours, then 60 hours). U / ml 1 hour, 37 ° C) to separate the cells from the tissue. The obtained cells were washed in RPMI 1640 / FCS.

Counting of all leukocytes obtained from the lumen of the airways and lung tissue was performed by an automated cell counter (Cobas Argos, US). Differential numbers of eosinophils, neutrophils, and mononuclear cells were read by light microscopy from cell preparations obtained by centrifugation stained by Vright-Giemz (Sigma, UK).

T lymphocytes were counted by flow cytometry (EPICS XL, Coulter Electronics, US) using fluorophore labeled anti-CD2 antibodies (a general T cell marker used for total T cell quantitation), CD4, CD8, and CD25 (activated T cell marker). All antibodies were supplied by Serotec Ltd., UK.

- 272

2.5 Data Analysis. · '

Cell data was expressed as the mean number of cells in the non-stimulated, stimulated and vehicle treated groups, and the stimulated and compound treated groups, including the mean error of the mean. Statistical analysis of the difference between treatment groups was evaluated using a one-factor analysis of variance by Mann-Vhitney test. No statistical significance was achieved at p <0.05.

Claims (99)

273 PATENT CLAIMS ·· · 9 9 · 9, 9 9 9999 advafcét NU νύ PRAGUE K, Kítatwi z A compound of formula I (I) wherein: R 1 represents a group selected from (i) R ³ -Z ³ (ii) R ³ -L ² -R ⁴ -Z ³ (iii) R ³ -L ³ -Ar ¹ -L ⁴ -Z ³ -, and (iv) R ³ -L ³ -Ar ¹ -L ² -R ⁴ -Z ³ -, - R ² is hydrogen, halogen, lower alkyl or lower alkoxy; R ³ represents alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkinyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkinyl, cycloalkenyl, heteroalalkenylalkyl, heteroloalkenylalkyl, heteroloalkenylalkyl, heteroloalkenylalkyl, , heteroarylalkinyl, heterocycloalkyl or heterocycloalkylalkyl; - 274 ·· · R ⁴ represents an alkylene group, an alkenylene group or an alkynylene group; R ³ represents a hydrogen atom or a lower alkyl group; r6 is hydrogen, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl or heteroarylalkyl; R? and R? ^and each independently of one another is hydrogen or lower alkyl; R ⁸ is hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocykloalkylaikylovou group; R ⁹ represents an alkyl group, an aryl group, a cycloalkyl group, a heteroaryl group or a heterocycloalkyl group or an alkyl group substituted with an aryl group, an acidic functional group, a cycloalkyl group, a heteroaryl group, a heterocycloalkyl group, -S (O) _m R ³ . O) -NY ⁴ Y ³ or -NY ⁴ Y ³ ; 1Π ^Υ R is hydrogen, R, or alkyl substituted with alkoxy, cycloalkyl, hydroxy, mercapto, alkylthio or -NY ⁴ Y ^5; 275 0 00 0 0 00 9 0 0 0 00 9 0 0 0,000 · 0 0 0000 0 0 0 0 0 • · • 0 0 0 · 00 00 0 0 · 0 R ¹¹ and R ¹³ independently of each other are selected from the group consisting of hydrogen and an amino acid side chain forming group, an acidic functional group, R ³ , -C (= O) -R ³ , or -C (= O) -NY ⁴ Y ³ , or an alkyl group substituted with an acidic functional group, R ³ , -NY ⁴ Y ³ , -NH-C (= O) -R ³ , -C (= O) -R ⁴ -NH 2, -C (= O) -Ar ¹ -NH 2, -C (= O) -R ⁴ -CO ₂ H, or -C (= O) -NY ⁴ Y ⁵ ; 'Or R ¹ ® and R ¹¹ or R ¹ ® and ^R12 together with the atoms to which they are attached form a three- to six-membered heterocycloalkyl ring, • R ^A · * represents an alkylene radical containing from 1 to 6 and carbon atoms, optionally substituted with R , R ¹⁴ is alkyl, aryl, arylalkyl, cycloalkyl, cykloalkylaikylovou, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl group; A ¹ represents a straight chain alkylene group having 1 to 3 carbon atoms, which is optionally substituted by one or more groups selected from the group consisting of alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, imino, oxo, z? thioxo, or alkyl substituted -zr, -ΝΥ Ύ ^ ^2, -CO ₂ R ⁶ or -C (= 0) ^ -ΝΥ Ύ ^2; Ar ¹ represents an arylene group or a heteroaryldiyl group; 4 ♦ · · · · • - 276 L ¹ represents (i) a direct bond, (ii) an alkenylene group, alkylene group, alkynylene group, cycloalkenylene group, cycloalkylene group, heteroaryldiyl group, heterocycloalkylene group or arylene group, each of which is optionally substituted with (a) an acidic functional group, cyano, oxo, -S (O) _m R ⁹ , R ³ , -C (= O) -R ³ , -C (= O) -OR ³ , -N (R ⁸ ) -C (= O) -R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ² R ⁹ , -NY ⁴ Y ⁵ or - [C (= O) -N (R ¹⁰ ) -C ( R ⁵ ) (R ¹¹ )] p C (= O) -NY ⁴ Y ⁵ , or (b) an alkyl substituted with an acidic functional group or -S (O) _m R ⁹ , -C (= O) -NY ⁴ Y ⁵ or -NY ⁴ Y ⁵ ; (iii) a - [C (= 0) -N (R ¹⁰⁾ -C (R ⁵⁾ (R ^11)] _p - connection, (iv) a -Z ² -R ¹² - connection; (v) -C (= O) -CH ₂ -C (= O) - linkage; (vi) -R ¹² -Z ² -R ¹² - linkage, (vii) -C (R ⁴ ) (R ¹³ ) - [C (= O) -N (R ¹⁰ ) -C (R ⁵ ) (R ¹¹⁾ )] _p - join or (viii) -L ⁵ -L ^ -L ² - join, L ² is -NR ⁵ -C (= Z) -NR ⁵ -, -C (= Z) -NR ⁵ -, -C (= O) -, -C (= Z) -O-, -NR ⁵ - C (= Z) -, -Z-, -SO ⁵ -, -NR ⁵ -, -SO ₂ -NR ⁵ -, -NR ⁵ -SO ₂ -, -NR ⁵ -C (= O) -O-, -0 -C (= O) -, or -O-C (= O) -NR ⁵ linkage, • 2 L is a heteroaryldiyl group, -NR ⁵ -C (= Z) -NR ⁵ -, -C (= Z) -NR ⁵ -, -C (= Z) -O-, -NR ⁵ -C (= Z) -, -Z-, -S0m-, -NR ⁵ -, -SO 2 NR ⁵ -, -NR ⁵ -SO ₂ -, -NR ⁵ -C (= O) -O-, -O-C (= O) -, or -O-C (= O) -NR ⁵ - join, L ⁴ represents a direct bond, an alkylene group, an alkenylene group or an alkynylene group; 277 '· · i ♦ ·· L ³ and L ² , independently of one another, are each a direct bond or an alkylene group, a cycloalkylene group or a heterocycloalkylene group, 1 9 Y and Y are each independently hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl, or -NY ^X Y may form a cyclic amine, Y ⁴ and Y ³ independently each represent hydrogen, alkenyl, alkyl, alkynyl, arylovou.skupinu, cycloalkenyl, cycloalkyl, heteroaryl, heterocycloalkyl, or alkyl substituted by alkoxy, aryl, cyano, , cycloalkyl, heteroaryl, heterocycloalkyl, hydroxy, oxo, -NY Y, or one or more -CO ₂ R or -C (= O) -NY 4 Y ² , or NY ⁴ Y ³ may be 5- to 5-membered a seven membered cyclic amine which (i) may be optionally substituted with one or more substituents selected from the group consisting of alkoxy, carboxamide, carboxy, hydroxy, oxo (or a five, six or seven membered cyclic acetal derivative thereof), R ¹⁰ ; . (ii) may also contain another heteroatom selected from the group consisting of O, S, SO ₂ , or NY 2; and (iii) can also be condensed to other aryl, I • · ♦ - 278 • φ 'φ Heteroaryl, heterocycloalkyl or cycloalkyl rings to form a bicyclic or tricyclic ring system, Y 0 represents a hydrogen atom, an alkyl group, an aryl group, an arylalkyl group -C (= O) -R ¹⁴ , -C (= O) -OR ¹⁴ or -SO ₂ R ¹⁴ , Z represents an oxygen or sulfur atom, Za is a group C (R ²⁾ (R ²⁾ C (= 0) or CH (OH); Z ² is O, S (O) _n , NR 6, SONR 6, C (= O) NR 6 or C (= O); Z ³ is a direct bond, C (= O), OC (= O), NR 4 C (= O), or SO ₂ ; , m is 1 or 2, n is zero or 1 or 2, and —p is zero or 1 to 4, Y represents a carboxy group (or bioisosteric acid), and the corresponding N-oxides and prodrugs thereof, and the pharmaceutically acceptable salts and solvates of these compounds and their N-oxides and prodrugs, but excluding compounds with oxygen, nitrogen or sulfur atoms attached directly to a carbon-carbon multiple bond of an alkenylene, alkynylene or cycloalkenylene residue. • 0 0 • · Λ '0 279 «· i 0 0 * 4 · 0 · * 0 0 0 0 0 • <t> 0 • · e A compound according to claim 1, wherein R 1 is a group R ³ -Z ³ -, wherein: Z ³ is C (= O) a R ³ represents an optionally substituted aryl group, an optionally substituted heteroaryl group, or an optionally substituted arylalkyl group. The compound of claim 2, wherein R is phenyl or phenyl substituted with one or two aryloxy, cyano, halogens, lower alkoxy, lower alkyl, nitro or CF 3. The compound of claim 2, wherein R is isoquinolinyl, isoxazolyl, pyrazolopyrimidinyl, pyridyl, pyrimidinyl, quinolinyl, thiazolyl and triazolyl, each of which may be optionally substituted with one or two groups selected from file including - alkylcarbonyl. an aryl group, an aryl group, a cyano group, halogens, a lower alkoxy group, a lower alkyl group, a lower alkylsulfonyl group, a lower alkylthio group, a nitro group and a CF3 group. A compound according to claim 2, wherein R is a benzyl group optionally substituted on the phenyl ring by one or two groups selected from the group consisting of halogens, hydroxy and methoxy groups. The compound of claim 2, wherein R ³ is 2-chlorophenyl, 5-chloro-2-cyanophenyl, 2-chloro-6-methylphenyl, 2,6-dichlorophenyl V (/ / _ · · · * · ♦ * · · · · · · · 9 9 · · 4 * · 9 9 ··· «« _f ř .. .. '280' 4 ·. _Ř . i, k, 2,6-difluorophenyl, 4-fluoro-2-trifluoromethyl, 2-methyl-4-nitrophenyl, 2-methyl-5-nitrophenyl, 2-nitrophenyl, 3-nitrophenyl or 2-phenoxyphenyl. The compound of claim 1, wherein R ¹ is a group R ³ -L ³ -Ar ¹ -L ⁴ -Z ³ -, wherein: Z ³ is C (= O), L ⁴ represents a straight-chain or branched alkylene group having 1 to 6 carbon atoms, Ar ¹ represents an optionally substituted phenylene group or an optionally substituted heteroaryldiyl group, L ³ is -NH-C (= O) -NH- R ³ represents an optionally substituted aryl group or an optionally substituted heteroaryl group. A compound according to claim 7, wherein: L ⁴ represents a methylene group, Ar ¹ represents an optionally substituted p-phenylene group a R ³ represents an optionally substituted phenyl group. A compound according to claim 8, wherein: Ar 1 represents p-phenylene or p-phenylene substituted in the 3-position by halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl or a (C 1 -C 4) alkylsulfonyl group, and R ³ represents a phenyl group substituted at the position - 281 9 9 9 9 9 9 · Is alkyl having 1 to 4 carbon atoms. A compound according to claim 1, wherein R ¹ represents a group R ¹ -L 1 -Ar 1 -L 1 -Z ³ -, wherein: Z ³ represents a C (= O) group, ΐΛ represents a straight or branched chain alkylene group containing 1 to 6 carbon atoms, Ar ¹ represents an optionally substituted 8 to 10 membered bicyclic system in which: a ring means a 5- or 6-membered heterocycle or a benzene ring, a ring is a 5- or 6-membered heterocycle or a benzene ring, the two rings being joined together by a carbon-carbon or carbon-nitrogen bond, 282 « L ³ is NH a R ³ represents an optionally substituted aryl group. The compound of claim 10, wherein: L ⁴ represents a methylene group and Ar ³ represents an optionally substituted benzoxazolyl group or an optionally substituted benzimidazolyl group. The compound of claim 11, wherein: Ar ³ means "benzoxazolyl or benzimidazolyl, each of which is optionally substituted with one or more groups selected from lower alkyl, lower alkoxy, amino, halogens, hydroxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl , nitro or trifluoromethyl, and R ³ represents a phenyl group substituted in the 2-position by lower alkyl, lower alkoxy, halogen ----------- or a (C 1 -C 4) dialkylamino group in each alkyl moiety. The compound of claim 1, wherein R ³ is a group R ³ -L ³ -Ar ³ -L ⁴ -Z ³ -, wherein: Z ³ is C (= O),. ·· L ⁴ represents a straight-chain or branched alkylene group having 1 to 6 carbon atoms, Ar ³ represents an optionally substituted phenylene group or an optionally substituted heteroaryldiyl group, L ³ is -C (= O) -NH- and R ³ is heterocycloalkyl. 283 The compound of claim 13, wherein: L ⁴ represents a methylene group and Ar 1 represents an optionally substituted p-phenylene group. The compound of claim 14, wherein: Ar 1 represents p-phenylene or p-phenylene substituted in the 3-position by halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl Or (C 1 -C 4) alkylsulfonyl, and R ³ represents an indolinyl group. A compound according to any one of the preceding claims, wherein R ² is a hydrogen atom. A compound according to any one of the preceding claims, wherein A ¹ is a straight chain unsubstituted alkylene group having 1 to 3 carbon atoms. The compound of claim 17, wherein A ¹ is a methylene group. The compound of claim 17, wherein A ¹ is an ethylene group. A compound according to any one of the preceding claims, in which it records CH ₂ , CHOH or C (= O). A compound according to any one of claim 20, wherein Z ¹ 284 is CH ₂ , A compound according to any one of the preceding claims wherein L ¹ is an optionally substituted alkylene group. The compound of claim 22, wherein L ¹ is an ethylene group or a propylene group, each optionally substituted with a lower alkyl group, an aryl group, a heteroaryl group, -N (R °) -C (= O) -RX -N (R ⁸ ) -C (= O) -OR ⁹ , -n (R ⁸ ) -so ₂ -r ⁹ , -ny ⁴ y ⁵ and - [C (= O) -N (R ¹⁰ ) -C (R ⁵ ) (R ¹¹ )] _p -C (= O) -NY ⁴ Y ⁵ or an alkyl substituted with a carboxy group (or an acidic bioisoster), -ZH, -ZR ³ , -C (= O) '- NY ⁴ Y ⁵ or -NY ⁴ Y ⁵ (wherein R ^3, R ^5, R ^8, R ^9, R ¹ ®, R ^11, Y ^4, Y-Z and p are as defined in claim 1). , 24- A compound of claim 22 in which L ¹ is' ⁵ • _________R -C-CH ₀ I R ¹⁵ in which: R @ ⁵ is hydrogen or lower alkyl, and R ^{± J} is hydrogen or lower alkyl, or R ⁵ is hydrogen and R ¹⁵ is aryl-Q, heteroaryl, -N (R °) -C (= O) -R ^y , -N (R) ⁸ ) -C (= O) -OR ⁹ , -n (R ⁸ ) -so ₂ -r ⁹ , -NY ⁴ Y ⁵ , _ [C (= O) -N (R ¹⁰ ) -C (R ⁵ ) (R ¹¹ )] p C (= O) -NY ⁴ Y ⁵ or is an alkyl group substituted with a carboxy group or an acidic bioisoster, or -ZH, -ZR ³ , -C (= O) -NY ⁴ Y ⁵ or - 285 • · 4 4 4 ··· 4 4 · 4444 · 4 4 _t • · 4 4 4 -NY ⁴ Y ⁵ (wherein R ³ , R ⁵ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , Z and p have the same meaning as in claim 1). The compound of claim 24, wherein it is a group Ř ¹⁵ in which: R - * - ⁵ represents a hydrogen atom, a lower alkyl group, an aryl group, a heteroaryl group, an -N (R ⁸ ) -C (= O) -R 7 group, -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ or -NY ⁴ Y ⁵ or a carboxy-substituted alkyl group, -OH, -OR ³ or -C (= O) -NY ⁴ Y ⁵ (wherein R ³ , R ⁸ , R ⁹ , Y ⁴ and Y ⁵ have the same meaning as in claim 1). 26. A compound according to claim 24, wherein it is a group (H-CH.> 15 in which: R ¹⁵ is hydrogen, lower alkyl, aryl, heteroaryl, -N (R ⁸ ) -C (= O) -R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ or -NY ⁴ Y ⁵ or a carboxy-substituted alkyl group, -OH, -OR ³ or -C (= O) -NY ⁴ Y ⁵ (wherein R ³ , R ⁸⁾ R ⁹ , Y ⁴ and Y ⁵ have the same meaning as in claim 1). A compound according to claim 22, wherein iA represents a group · 286 * · · ftft · ft · ftft · ftft ftft •••• «ftft · • · ftft 9 '· ·' ft · 'ft -C-CH-I R ^15a in which: R ³ is hydrogen or lower alkyl, and Rl5a _known and _en-lower alkyl, or R ³ is hydrogen and R ^43a represents aryl, QQ, heteroaryl, -N (R) -C (= O) -R, -N (R ⁸⁾ -C (= O) -OR ^9, -N (R ⁸⁾ -SO ₂ -R ^9, -ny ⁴ y ⁵ , - [C (= O) -N (R ¹⁰ ) -C (R ³ ) (R 6)] p C (= O) -NY ⁴ Y ³ or is an alkyl group substituted with a carboxy group or an acidic bioisoster, or -ZH, -ZR ³ , -C (= O) -NY ⁴ Y ³ or -NY ⁴ Y ³ (wherein R ³ , R ³ , R ⁸ , R ⁹ , R 6 -θ, R 6, Y ⁴ , Y ³ , Z and p have the same meaning as in claim 1). The compound of claim 27, wherein ΐΛ is a group H ₂ —CH— Řl ^5a in which: R 15a represents a group -N (R ⁸ ) -C (= O) -R ⁹ or -N (R ⁸ ) -SO ₂ -R ⁹ (in which R ⁸ and R ⁹ have the same meaning as in claim 1). The compound of claim 27, wherein L ¹ is a group 15a 287 wherein: R ^15a is -N (R ⁸ ) -C (= O) -R ⁹ or -N (R ⁸ ) -SO ₂ -R ⁹ (wherein R ⁸ and R ⁹ have the same meaning as in claim 1). A compound according to any one of the preceding claims wherein Y is carboxy. A compound according to claim 1 having the general formula (Ia): wherein R ² , R ³ , Ar ¹ , A 1, L ⁴ , Y and the same meaning as defined above in the corresponding claims, and the corresponding N-oxides and prodrugs thereof, and the pharmaceutically acceptable salts and solvates thereof compounds and their N-oxides and prodrugs. A compound according to claim 1 having the general formula (Ib): r 288 ··· '0 9 · ♦ • ♦ ··· · · in which: R ² , R ³ , A ¹ , L ² , Y and Z ¹ have the same meaning as defined in the corresponding claims above, X is NR ³ or O, Z ⁴ represents a direct bond, NR ³ , O or S (O) _n (wherein R ³ and _n have the same meaning as defined in the corresponding claims above), and R represents a hydrogen atom or a substituent of an aryl group, and the corresponding N-oxides and prodrugs thereof, and pharmaceutically acceptable salts and solvates thereof, and N-oxides and prodrugs thereof. A compound according to claim 1 having the general formula (Ic): wherein Ar ¹ , L ⁴ , A ¹ , R ² , L ¹ , Y and Z ¹ have the same meaning as previously defined in the corresponding claims, i.e. and the corresponding N-oxides and prodrugs thereof, and pharmaceutically acceptable salts and solvates thereof, and N-oxides and prodrugs thereof. A compound according to claim 1 having the general formula (Id): 289 Id Wherein R, A, R, LY and Z have the same meaning as previously defined and the corresponding N-oxides and prodrugs thereof, and pharmaceutically acceptable salts and solvates thereof and N-oxides and prodrugs thereof . The compound of claim 31, wherein R is phenyl substituted at the 2-position with C 1-4 alkyl. A compound according to any one of claims 31, 33 and 35, wherein Ar · ¹ represents a p-phenylene group or a p-phenylene group substituted at the 3-position by halogen, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group. (C 1 -C 4) alkylthio, (C 1 -C 4) alkylsulfinyl, or (C 1 -C 4) alkylsulfonyl, α The compound of claim 32, wherein R is phenyl substituted at the 2-position by lower alkyl, lower alkoxy, halogen, or dialkylamino containing from 1 to 4 carbon atoms in each alkyl moiety. 290 • ·· ··· 9 9 · · í · · ·· ·. · · · 9-9 · 9 · • · '· ^· · ^l · ·· ···· «« · _»e • · ·· · 9 9 9 9 A compound according to claim 32 or 37, wherein Z ⁴ is NH. A compound according to any one of claims 32, 37 and 38, wherein R is hydrogen, halogen, lower alkyl or lower alkoxy. A compound according to any one of claims 31, 32, 33 and 35 to 39, wherein L ⁴ is a straight or branched chain alkylene group having 1 to 4 carbon atoms. , The compound of claim 40, wherein L ⁴ is a methylene group. ’A The compound of claim 34, wherein R is phenyl or phenyl substituted with one or two aryloxy, cyano, halogens, lower alkoxy, lower alkyl, nitro or CF 3. «'. ř, The compound of claim 34, wherein R ³ is a benzyl group optionally substituted on the phenyl ring with one or two halogens, hydroxy, or methoxy groups. and A compound according to claim 34, wherein R is 2-chlorophenyl, 5-chloro-2-cyanophenyl, 2-chloro-6-methylphenyl, 2,6-dichlorophenyl, 2,6-difluorophenyl, 4-fluoro-2-trifluoromethyl, 2-methyl-4-nitrophenyl, 2-methyl-5-nitrophenyl, 2-nitrophenyl, ·. · - 291 3-nitrophenyl or 2-phenoxyphenyl. A compound according to any one of claims 31 to 44, wherein A 1 is a straight chain unsubstituted alkylene group having 1 to 3 carbon atoms. The compound of claim 45, wherein A ¹ is a methylene group. . The compound of claim 45, wherein A 1 is an ethylene group. A compound according to any one of claims 31 to 47, wherein zA is CH ₂ . A compound according to any one of claims 31 to 48, wherein it is hydrogen. * A compound according to any one of claims 31 to 49, wherein iA is an optionally substituted alkylene group. . , A compound according to claim 50, wherein iA represents an ethylene group or a propylene group, each optionally substituted by a lower alkyl group, an aryl group, a heteroaryl group, -N (R 0) -C (= O) -R 3, -N (R ⁸ ) -C (= O) -OR ⁹ , -n (R ⁸ ) -so ₂ -r ⁹ , -ny ⁴ y ⁵ and - [C (= O) -N (R ¹⁰ ) -C (R ⁵ ) (R ¹¹ )] _p -C (= O) -NY ⁴ Y ⁵ or an alkyl substituted with a carboxy group (or an acidic bioisoster), -ZH, -ZR ³ , -C (= O) -NY ⁴ Y ⁵ or -NY ⁴ Y ³ (wherein R ³ , R ³ , R ⁸ , R ⁹ , R ¹¹ , r H, Y ⁴ , Y ⁵ , Z and p have the same meaning as in claim 1). 292 · · · ··· · The compound of claim 50, wherein L ¹ is a group wherein: R ³ is hydrogen or lower alkyl, and R @ ¹ is hydrogen _lower alkylene or lower alkyl, or R ³ is hydrogen and R ¹⁵ is aryl A QQ group, a heteroaryl group, a group -N (R °) -C (= O) -R, -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ , -NY ⁴ Y ⁵ , - [C (= O) -N (R ¹⁰ ) -C (R ⁵ ) (R ¹¹ )] p C (= O) -NY ⁴ Y ³ or is an alkyl group substituted by carboxy or an acidic bioisoster, or by -ZH groups , -ZR ³ , -C (= O) -NY ⁴ Y ³ or -NY ⁴ Y ³ (wherein R ³ , R ³ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ ,, Υ ⁴ , Y ⁵ , Z and p have the same meaning as in claim 1). The compound of claim 52, wherein L ¹ is a group H — CH in which :, R ¹⁵ is hydrogen, lower alkyl, aryl, heteroaryl, -N (R ⁸ ) -C (= O) -R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , - N (R ⁸ ) -SO ₂ -R ⁹ or -NY ⁴ Y ³ or a carboxy-substituted alkyl group, -OH, -OR ³ or -C (= O) -NY ⁴ Y ³ (wherein R ³ , R ⁸ , R ⁹ , Y ⁴ and Y ³ have the same meaning as in claim 1). 99 · 293 The compound of claim 52, wherein L ^x is a group ZH — CH in which: R ¹³ is hydrogen, lower alkyl, aryl, heteroaryl, -N ^(R8) -C (= O) ^-R9, -N ^(R8) -C (= O) -OR ^9, - N (R ⁸ ) -SO ₂ -R ⁹ or -NY ⁴ Y ⁵ or a carboxy-substituted alkyl group, -OH, -OR ³ or -C (= O) -NY ⁴ Y ⁵ (wherein R ³ , R ⁸ , R ⁹ , Y ⁴ and Y ³ have the same meaning as in claim 1). The compound of claim 50, wherein ΐΛ is a group R ³ AND -C-CH-I R ^15a in which: R ³ is hydrogen or lower alkyl, and R ^13a is lower alkyl, or r 5 is hydrogen and R ^15a is aryl of O, heteroaryl, -N (R 0) -C (= O) -R, -N (R ⁸ ) -C (= O) -OR ^9, -N (R ⁸⁾ -SO ₂ -R ^9, -NY ⁴ Y ^5, - [C (= O) -N (R ¹⁰ ) -C (R ⁵ ) (R ¹¹ )] _p -C (= O) -NY ⁴ Y ⁵ or is an alkyl group substituted with a carboxy group or an acidic bioisoster, or -ZH groups , -ZR ³ , -C (= O) -NY ⁴ Y ³ or -NY ⁴ Y ⁵ (wherein R ³ , R ⁵ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , Y ⁴ , Y ⁵ , Z and p have the same meaning as in claim 1). The compound of claim 55, wherein L ¹ is 294 • 0 0 0 0 • 0000 group: h ₉ —CH— AND In which: Rl5a _znam Measured -N (R ⁸⁾ -C (= 0) -R ⁹ or -N (R ⁸⁾ -SO ₂ -R ⁹ (wherein R ⁸ and R ⁹ are as defined in claim 1). The compound of claim 55, wherein L ¹ is a group wherein: R ^3a is -N (R ⁸ ) -C (= O) -R ⁹ or -N (R ⁸ ) -SO ₂ -R ⁹ (wherein R ⁸ and R ⁹ have the same meaning as in claim 1). A compound according to any one of the preceding claims wherein Y is carboxy. A compound of formula (Ia) according to claim 31, wherein: R ² is hydrogen, R ³ represents a 2-substituted phenyl group, denotes a methylene group or an ethylene group, Ar 1 represents an optionally substituted m-phenylene or p-phenylene group or an optionally substituted p-pyridinediyl group, - 295 • 00 * 0 0 0 • 0 00 · ·· 00 00 00 00 00 00 0 0 00 0 L ¹ represents a group -CH — CH ₇ - R 15 [wherein R ¹³ is hydrogen, lower alkyl, aryl, heteroaryl, -N (R ⁸ ) -C (= O) -R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ or -NY ⁴ Y ^3, or an alkyl group substituted with a carboxy group (or an acidic bioisoster), -OH, -OR ^3, or -C (= O) -NY ⁴ Y ³ ], L ⁴ represents a straight or branched chain alkylene group having 1 to 6 carbon atoms, Y is carboxy, and Z ¹ is CH ₂ , and the corresponding N-oxides and prodrugs thereof, and pharmaceutically acceptable salts and solvates thereof, and N-oxides and prodrugs thereof. A compound of formula (Ia) according to claim 31, wherein: R is hydrogen, R ³ represents a 2-substituted phenyl group, A ¹ represents a methylene group or an ethylene group, Ar ¹ represents an optionally substituted m-phenylene or p-phenylene group or an optionally substituted p-pyridinediyl group, L ¹ represents a group -CHo — CH— AND R ^13a [wherein R ^13a is -N (R ⁸ ) -C (= O) -R ⁹ or 9 «· 296 -N (R ⁸ ) -SO ₂ -R ⁹ ], L ⁴ represents a straight or branched chain alkylene group having 1 to 6 carbon atoms, Y is carboxy, and is CH ₂ , and the corresponding N-oxides and prodrugs thereof, and pharmaceutically acceptable salts and solvates thereof, and N-oxides and prodrugs thereof. A compound of formula (1b) according to claim 32, wherein: R represents a hydrogen atom, a chlorine atom, a methyl group, an ethyl group or a methoxy group, R ² is hydrogen, R ³ represents a substituted aryl group, A ¹ represents a methylene group or an ethylene group, L ¹ represents a group -CH — CH? - I, R ¹⁵ [wherein R ^1-3 is hydrogen, lower alkyl, aryl, heteroaryl, -N (R ⁸ ) -C (= O) -R ⁹ , -N (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ or -NY ⁴ Y ³ or a carboxy-substituted alkyl group (or an acidic bioisoster), -OH, -ZR ³ , -C (= O) -NY ⁴ Y ³ or -NY ⁴ Y ⁵ ], L ⁴ represents a straight or branched chain alkylene group having 1 to 4 carbon atoms, X is 0, Y is carboxy, and Z ¹ is CH ₂ , 297 9 9 9 9 9 9 9 9 9 10 11 12 13 14 15 16 17 · · Z ⁴ is NH, and the group is attached to the 6-position of the ring, and the corresponding N-oxides and prodrugs thereof, and pharmaceutically acceptable salts and solvates of these compounds, and N-oxides and prodrugs thereof. A compound of formula (Ib) according to claim 32, wherein: R represents a hydrogen atom, a chlorine atom, a methyl group, an ethyl group or a methoxy group, R ² is hydrogen / R ³ is an optionally substituted group, A ¹ represents a methylene group or an ethylene group, 1A represents a group -CH _O —CH— _R 15a [wherein R ^15a is -N (R ⁸ ) -C (= O) -R ⁹ or -N (R ⁸ ) -SO ₂ -R ⁹ ], L ⁴ represents a straight or branched chain alkylene group having 1 to 4 carbon atoms, X is O, Y is carboxy, Z2 represents a CH ₂ group, 298 Z ⁴ is NH, and the group is attached to the 6-position of the ring, and the corresponding N-oxides and prodrugs thereof, and pharmaceutically acceptable salts and solvates of these compounds, and N-oxides and prodrugs thereof. A compound of formula (Ib) according to claim 32, wherein: means a hydrogen atom, R ³ represents an optionally substituted group, A ³ represents a methylene group or an ethylene group, L ³ represents a group: h - ch ₉ - ^z [wherein R ³⁵ represents a hydrogen atom, a lower alkyl group, an aryl group, a heteroaryl group, an -N (R ⁸ ) -C (= O) -R ⁹ , -N ( R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ or -NY ⁴ Y ³ or an alkyl group substituted with a carboxy group (or an acidic bioisoster), -OH, -OR ³ , - C (= O) -NY ⁴ Y ³ or -NY ⁴ Y ⁵ ], L ⁴ represents a straight or branched chain alkylene group having 1 to 4 carbon atoms, X is NR ^5, 299 • Η • · .0 0 0 • · · · • • • 0 0 0 0 • »· • 0 • 9 • • • · · · ·! * • 999 9 • 0 0 • · · 0 0 • · 0 00 0 0 Y is carboxy, Z ² is CH _2, Z ⁴ is NH, and the group is attached to the 5 or 6 position of the ring, and the corresponding N-oxides and prodrugs thereof, and pharmaceutically acceptable salts and solvates of these compounds, and N-oxides and prodrugs thereof. A compound of formula (Ib) according to claim 32, wherein: 9 χ ^T R is hydrogen, R ³ represents optionally substituted aryl, A ¹ is methylene or ethylene, ΐΛ is -CH -CH- _O I _R i5a [in which R ^3a represents a group -N (R ⁸⁾ -C (= 0) -R ⁹ or -N (R ⁸ ) -SO ₂ -R ⁹ ], L ⁴ represents a straight or branched chain alkylene group having 1 to 4 carbon atoms, X is NR ^3, Y is carboxy, and Z ¹ is CH ₂ , Z ⁴ is NH, 'i} · carboxylate 300 • 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 · 99 99 9 9999 · 9 · 9 • 9 9 9 · 999 · 9 · · 9 99 9 9 9 9 9 is attached to position 5 or 6 of the ring, and the corresponding N-oxides and their prodrugs, and further pharmaceutically acceptable salts and solvates of these compounds and their N-oxides and prodrugs. A compound of formula (Ic) according to claim 33, wherein: R ² is hydrogen, A ¹ represents a methylene group or an ethylene group, Ar ¹ represents an optionally substituted m-phenylene or p-phenylene group or an optionally substituted p-pyridinediyl group, 1A represents a group Ή — CH ₂ -, 15 [wherein R ¹³ is hydrogen, methyl, aryl, heteroaryl, -N (R ⁸ ) -C (= O) -R ⁹ , - N (R ⁸ ) - C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ or -NY ⁴ Y ³ or a carboxy-substituted alkyl group, -OH, -OR ³ or -C (= O) -NY ⁴ Y ³ ], L ⁴ represents a straight or branched chain alkylene group having 1 to 4 carbon atoms, Y is carboxy, and 301 Zp is CH ₂ , and the corresponding N-oxides and prodrugs thereof, and pharmaceutically acceptable salts and solvates thereof, and N-oxides and prodrugs thereof. A compound of formula (Ic) according to claim 33, wherein: R ² is hydrogen, A 1 represents a methylene group or an ethylene group, Ar 2 is an optionally substituted m-phenylene or p-phenylene group, or an optionally substituted p-pyridinediyl group, ΐΛ represents a group -CH _O —CH— AND R ^15a [wherein R ^23a is -N (R ⁸ ) -C (= O) -R ⁹ or R ^15a -N (R ⁸ ) -SO ₂ -R ⁹ ], L ⁴ represents a straight or branched chain alkylene group having 1 to 4 carbon atoms, Y is carboxy, and Zp is CH ₂ , and the corresponding N-oxides and prodrugs thereof, and pharmaceutically acceptable salts and solvates thereof (such as hydrates) and N-oxides and prodrugs thereof. A compound of formula (Id) according to claim 34, wherein: R ² is hydrogen, R ³ represents an optionally substituted phenyl group; - 302 optionally substituted heteroaryl or optionally substituted benzyl, A 1 represents a methylene group or an ethylene group, A 1 represents a group -CH — CH ₀ - R ¹⁵ [wherein R ¹⁵ is hydrogen, methyl, aryl, heteroaryl, -N (R ⁸ ) -C (= ObR ⁹⁾ , Jn (R ⁸ ) -C (= O) -OR ⁹ , -N (R ⁸ ) -SO ₂ -R ⁹ or -NY ⁴ Y ³ or a carboxy-substituted alkyl group, -OH, -OR ³ or -C (= O) -NY ⁴ Y ³ ], Y is carboxy, and, is CH ₂ ,. and the corresponding N-oxides and prodrugs thereof, and pharmaceutically acceptable salts and solvates thereof (such as hydrates) and N-oxides and prodrugs thereof. A compound of formula (Id) according to claim 34, wherein: R ² is hydrogen, R ³ represents an optionally substituted phenyl group, an optionally substituted heteroaryl group, or an optionally substituted benzyl group, A ¹ represents a methylene group or an ethylene group, iA represents a group H ₂ —CH— R ^15a 303 »· · · · 9 · 9 · 9 · 9 · 999 9 9 9999> 9999> 999 · 9 99 • 9 9 9 9 9 9 9 9 9 9 9 9 • «[in which represents a radical -N (R ⁸⁾ -C (= O) -R ⁹ or -N (R ⁸ ) -SO ₂ -R ⁹ ], Y is carboxy, and is CH ₂ , and the corresponding N-oxides and prodrugs thereof, and pharmaceutically acceptable salts and solvates thereof (such as hydrates) and N-oxides and prodrugs thereof. A compound according to any one of claims 60, 62, 64, 66 and 68, wherein ΐΛ is -CH. : h— 15a A compound according to any one of claims 61, 63, 65, and 67, wherein L ¹ is a group -CH? —CH— i R ^15a The compound of claim 70, wherein R ¹³ is hydrogen. A compound according to claim 70, wherein R ¹⁵ is lower alkyl. The compound of claim 70, wherein R ¹⁵ is an optionally substituted phenyl group. - 304 74. A compound according to claim 70 wherein is -N (R ⁸ ) -C (= O) -R ⁹ wherein R ⁸ is hydrogen or lower alkyl and R ⁹ is lower alkyl, aryl, heteroaryl, alkoxy-substituted alkyl, carboxy-substituted alkyl or an alkyl group substituted with -NY ⁴ Y ⁴ . A compound according to claim 70, wherein R 6 is -N (R ⁸ ) -C (= O) -OR ⁹ , wherein R ⁸ is hydrogen or lower alkyl and R ⁹ is lower alkyl or substituted alkyl aryl group. A compound according to claim 70, wherein R ³ is -N (R ⁸ ) -SO ₂ -R ⁹ , wherein R ⁸ is hydrogen or lower alkyl and R ⁹ is lower alkyl, aryl or heteroaryl. The compound of claim 70, wherein R ¹³ is -NY ⁴ Y ³ , wherein Y ⁴ and Y ⁴ are hydrogen. The compound of claim 70, wherein R ¹⁵ is-znamená ⁴ γ ⁵ , wherein Y ⁴ is hydrogen and Y 4 is lower alkyl or alkyl substituted with aryl. 1 sec The compound of claim 70, wherein R ^XJ is -NY ⁴ Y ³ , wherein Y ⁴ and Y ⁵ are both aryl. 80. The compound of claim 70 in which R ¹ · - ^ is lower alkyl substituted with carboxy. 305 The compound of claim 70, wherein R ¹³ is a lower alkyl group substituted with -OH. The compound of claim 70, wherein R ¹³ is a lower alkyl group substituted with -OR ³ . The compound of claim 70, wherein R ¹³ is a lower alkyl group substituted with -C (= O) -NY ⁴ Y ⁵ . The compound of claim 70, wherein R ¹³ is O O O H II 'II -NH — C — CH — CH — COH, NH — C — CH — CH — CH — COH, —NH — C — CH — NH4, / - \ -NH — C-CH3-N- P, o II -CH — C — N \ _O, -CH-C1-Me, //, R R (in which R represents a hydrogen atom or a substituent of an aryl group),. —Ch ₃ , —ch ₂ ch ₃ , —ch ₂ ch ₂ ch ₃ , —ch ₂ ch ₂ ch ₂ ch ₃ , —CH ₂ —OH, —CH ₂ —CO ₂ H or —CH ₂ —OMe A compound according to claim 69. in which, R stands for O Q -N (R °) -C (= O) -R wherein R is hydrogen or lower alkyl and R ⁹ is lower alkyl, aryl, heteroaryl, alkoxy substituted alkyl, carboxy substituted alkyl or alkyl a group substituted with -NY ⁴ Y ⁴ . 86. The compound according to claim 69, wherein R ^^ ^and it is -N (R °) -C (= O) -R wherein R is hydrogen or lower alkyl and R ⁹ is selected from 2-chlorophenyl, 5-chloro-2-cyanophenyl, 2-chloro -6-methylphenyl, 2,6-dichlorophenyl, 2,6-difluorophenyl, 307 • 9 9 10 » 9 • 9 9 • • • · • • 9 • 999 '9 · • 9999 • · 9 • '9 9 • • • 9 99 · 100 · » * • • '9 4-fluoro-2-trifluoromethyl, 2-methyl-4-nitrophenyl, 2-methyl-5-nitrophenyl, 2-nitrophenyl, 3-nitrophenyl and 2-phenoxyphenyl. A compound according to claim 69 wherein R ^33a is -N (R ⁸ ) -C (= O) -R ⁹ wherein R ⁸ is hydrogen or lower alkyl and R ⁹ is selected from quinolin-4 -yl, isoquinolin-2-yl, 2,4-pyridin-3-yl, 2,6-dimethyl-4-trifluoromethylpyridin-3-yl; A 4-trifluoromethylpyridin-3-yl group, A 2-phenyl-4-methyl-1,2,3-triazol-5-yl group, 3,5-dimethylisoxazol-4-yl; A 2,7-dimethylpyrazolo [1,5-a] pyrimidin-6-yl group, A 2-isopropyl-4-methylthiazol-5-yl group and a 4-trifluoromethylpyrimidin-5-yl group. 88. A compound according to claim 1 selected from the group consisting of: 3- (1 - {[3-methoxy-4- (3- [2-methylphenyl] -ureido) -phenyl] -acetyl} -1,2,3,4-tetrahydroquinolin-6-yl) -propionic acid 3- (1 - {[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl} -2,3-dihydro-1H-indol-5-yl) -butyric acid 3- ( 1 - {[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl} -1,2,3,4-tetrahydroquinolin-6-yl) butyric acid 3- (1- { [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl} -2,3-dihydro-1H-indol-5-yl) pentanedioic acid, 308 - 3- (1 - {[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl} -1,2,3,4-tetrahydro-quinolin-6-yl) -pentanedioic acid , 4- [2-carboxy-1- (1 - {[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl} -1,2,3,4-tetrahydroquinoline-6- yl) ethylcarbamoyl] -butyric acid N- [2-carboxy-1- (1 - {[3-methoxy-4- (3-o-tolylureido) phenyl) acetyl} -1,2,3,4- 3- (1 - {[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl} -1,2,3,4-tetrahydroquinolinic acid, tetrahydroquinolin-6-yl) ethyl -6-yl) -3 - [(5-methyl-isoxazole-3-carbonyl) -amino] -propionic acid 2- (2-chloro-6-methyl-benzoylamino) -3- [1- (2,6) 2- (2,6-dichloro-benzoylamino) -3- [1- (2,6-dichloro-benzoyl) -dichloro-benzoyl) -1,2,3,4-tetrahydroquinolin-6-yl] -propionic acid -1,2,3,4-tetrahydroquinolin-6-yl) -propionic acid 3- (1 - {[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl} -2, 3-Dihydro-1H-indol-5-yl) -3-phenyl-propionic acid; 3- (1 - {[3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetyl} -2,3-dihydro-1H-indol-5-yl) -pentanoic acid; and the corresponding N-oxides or prodrugs thereof, or pharmaceutically acceptable salts or solvates thereof (such as hydrates) or N-oxides or prodrugs thereof. ·· · 309 89. Compounds of formulas (IV), (IX) and (2) as intermediates. 90. A pharmaceutical composition comprising in an effective amount a compound of claim 1 or a corresponding N-oxide or prodrug thereof, or a pharmaceutically acceptable salt or solvate thereof, or an N-oxide or prodrug thereof, in association with a pharmaceutically acceptable salt thereof. an acceptable carrier or excipient. A compound according to claim 1 or a corresponding N-oxide or prodrug thereof, or a pharmaceutically acceptable salt or solvate thereof, or an N-oxide or prodrug thereof, for use in therapy. A compound according to claim 1 or a corresponding N-oxide or prodrug thereof, or a pharmaceutically acceptable salt or solvate thereof, or an N-oxide or prodrug thereof, for use in treating a patient suffering from or susceptible to a disease state that may be attenuated by administration of α4β1-mediated cell adhesion inhibitor. 93. The pharmaceutical composition of claim 90 for use in treating a patient suffering from or susceptible to a disease state that can be alleviated by administering an α4β1 mediated cell adhesion inhibitor. The compound or composition of claim 1 or 90 for use in the treatment of inflammatory diseases. The compound or composition of claim 1 or 91 310 '' ········· «···· 7 ······· for use in the treatment of asthma. 96. The use of a compound according to claim 1 or a corresponding N-oxide or prodrug thereof, or a pharmaceutically acceptable salt or solvate thereof, or N-oxide or prodrug thereof for use in the manufacture of a medicament for treating a patient suffering from or susceptible to a disease state. ¹ which may be alleviated by administration of an inhibitor of α4β1 mediated cell adhesion. Use of a compound according to claim 1 or a corresponding N-oxide or prodrug thereof, or a pharmaceutically acceptable salt or solvate thereof, or an N-oxide or prodrug thereof, for use in the manufacture of a medicament for the treatment of asthma. 98. A method of treating a human individual as a patient or a non-human individual suffering from a disease or susceptible to a disease state which may be alleviated by administering an α4β1 mediated cell adhesion inhibitor comprising administering to said patient an effective amount of a compound of claim 1 or a corresponding N-oxide or prodrug thereof, or a pharmaceutically acceptable salt or solvate thereof, or an N-oxide or prodrug thereof. 99. A compound substantially described in this specification with reference to Examples.