Bicyclosulphonyl acid (bcsa) and use thereof as therapeutic agent

FIELD: chemistry.

SUBSTANCE: invention relates to bicyclosulphonyl acid (BCSA) compounds of formula: where: where each of -Rpw, -Rpx, -RPY, and -RPZ independently denotes H or -RRS1; each -RRS1 independently denotes -F, -Cl, -Br, -I, -RA1, -CF3, -OH, -OCF3 or -ORA1; where each RA1 independently denotes C1-4alkyl, phenyl or benzyl; and additionally, two neighbouring -RRS1 groups can together form -OCH2O-, -OCH2CH2O- or -OCH2CH2CH2O-; -RAK independently denotes a covalent bond, -(CH2)- or -(CH2)2-; -RN independently denotes -RNNN, or -LN-RNNN; the rest of the values of the radicals are given in claim 1, which act as inhibitors of inhibitors of tumor necrosis factor-α converting enzyme (TACE).

EFFECT: compounds are useful in treating TNF-α mediated conditions.

36 cl, 303 ex

 

A RELATED APPLICATION

This application is a related Application U.S. Patent number 60/924518, registered on may 18, 2007, the contents of which are fully incorporated into the present application by reference.

The technical FIELD

The present invention generally relates to the field of therapeutic compounds, and more specifically to certain compounds that are derived bicycloalkyl acid (BCSA), acting as inhibitors of the enzyme that catalyzes the formation of tumor necrosis factor-α (Tumour Necrosis Factor-α Converting Enzyme, TACE). Compounds according to the present invention are useful for treating conditions mediated by tumor necrosis factor-α (TNF-α), such as rheumatoid arthritis; inflammation; psoriasis; septic shock; rejection of the implant; cachexia; anorexia; congestive heart failure; postischemic injury associated with reperfusion injury; inflammatory disease of the Central nervous system, inflammatory bowel disease; insulin resistance; HIV infection; cancer; chronic obstructive pulmonary disease (COPD) or asthma. The present invention also relates to pharmaceutical compositions that contain these compounds and the use of such compounds and compositions, both in vitro and in vivo for inhibition of TACE and treatment condition is, which is better with the inhibition of TACE.

PRIOR art

For a more complete description and disclosure of the invention and prior art to which the present application, in the present description cited a number of patents and publications. The content of each of these publications and patents are fully incorporated in the present description by reference, as if independently in this description included the content of each individual cited in the document.

Throughout the present description, including the following claims, unless the context indicates otherwise, the word "include/contain" and variations such as "includes/contains" and "comprising/containing" should be understood as the inclusion of a specified entity or step, or group of entities or stages, but not as an exception to any other entity or step, or group of entities or stages.

It should be noted that in the description and the attached claims used the singular number also include the corresponding plural forms unless the context clearly indicates otherwise. So, for example, reference to "a pharmaceutical carrier" includes mixtures of two or more such carriers, and the like.

In the present description ranges often expressed in the de from "about" one particular value and/or to "about" another particular value. When the range is represented in this form, other implementations include a range of specified values and/or to another specified value. Similarly, if values are approximated, the use of the phrase "approximately" should be interpreted in such a way that a specific value is included in other embodiments of the present invention.

TAS

TAS (the enzyme that converts in TNF-α) catalyzes the formation of TNF-α (tumor necrosis factor-α) of the membrane-associated protein precursor of TNF-α. TNF-α is a proinflammatory cytokine, which, as some believe plays a role in numerous diseases, including the following:

rheumatoid arthritis (see, for example, Shire et al., 1998; Isomaki et al., 1997; Camussi et al., 1998);

inflammation (see, for example, Ksontini et al., 1988);

psoriasis (see, e.g., Le et al., 2005; Palladino et al., 2003);

septic shock (see, for example, Mathison et al.,1988, Miethke et al., 1992);

rejection of the implant (see, for example, Piguet et al., 1987;

cachexia (see, e.g., Beutler et al., 1988);

anorexia (see, for example, Schattneret al., 1990);

congestive heart failure (see, e.g., Packer et al., 1995; Ferrari et al., 1995);

postischemic injury associated with reperfusion (see, for example, Gu et al., 2006);

inflammatory disease of the Central nervous system (see, for example, Grau et al., 1987);

inflammatory disease of the to the of Chechnya (see, for example, McDonald et al., 1990);

insulin resistance (see, for example, Hotamisligil et al., 1993);

HIV infection (see, e.g., Peterson et al., 1992; Pallares-Trujillo et al., 1995);

cancer (see, for example, Old, 1985);

chronic obstructive pulmonary disease (COPD) or asthma (see, for example, Trifilieff et al., 2002).

Additional examples of such diseases include osteoarthritis, ulcerative colitis, Crohn's disease, multiple sclerosis and degenerative loss of cartilage.

Several research groups have synthesized derivatives of hydroxamic acid containing sulfonamidnuyu group, as potential antiproliferative and anti-inflammatory agents (see, for example, Levin et al., 1999; Ohtani et al., 1993; Owen et al., 2000, Yu et al., 2006).

Although the number of known inhibitors of TACE, many of these compounds are peptides or analogues of peptides, the disadvantages of which are problems with bioavailability and pharmacokinetic profile. In addition, many of these compounds show no selectivity as powerful inhibitors of metalloprotease matrix, in particular MMP-1 (collagenase 1). On the basis of clinical trials of inhibitors of metalloprotease suggest that MMP-1 causes pain in the joints (see, for example, Scrip, 1988).

Thus, with a long action, selective, bioavailable when administered orally, nepat the derivative inhibitors of TACE are highly desirable for the treatment of the above conditions.

SUMMARY of the INVENTION

One aspect of the present invention relates to certain derivatives "bicycloalkyl acid (BCSA), described in this application.

Another aspect of the invention disclosed in this application relates to a pharmaceutical composition, which contains a derivative BCSA, as well as pharmaceutically acceptable carrier, diluent or excipient.

Another aspect of the present invention disclosed in this application relates to a method for preparing a pharmaceutical composition, comprising mixing derived BCSA described in this application, and a pharmaceutically acceptable carrier, diluent or excipient.

Another aspect of the present invention described in this application, refers to a derivative BCSA for use in the method of treatment (e.g., disease or disorder) of the human body or animal body by therapy.

Another aspect of the present invention described in this application refers to the application of the derived BCSA in the manufacture of a medicine for treatment (e.g., disease or disorder) of a human or animal.

Another aspect of the present invention described in this application relates to a method of treatment (for example, diseases or disorders), VK is causea introduction to the patient, in need of a specific treatment, a therapeutically effective amount of BCSA, preferably in the form of pharmaceutical compositions.

In one implementation of the present invention said treatment is the treatment of diseases or disorders mediated by TACE, for example, a disease or disorder, about which it is known that it is mediated by TACE.

In one embodiment, the implementation of the said treatment is the treatment of a disease or disorder, the symptoms of which can be improved by inhibition of TACE, for example, a disease or disorder, about which it is known that the symptoms of this condition can be improved by inhibition of TACE.

In one embodiment, the implementation of the said treatment is the treatment of a disease or disorder that is treated by TACE inhibitor, such as a disease or disorder, about which it is known that it is treated by TACE inhibitor.

In one embodiment, the implementation of the said treatment is the treatment of rheumatoid arthritis; inflammation; psoriasis; septic shock; graft rejection; cachexia; anorexia; congestive heart failure; postischemic injury associated with reperfusion injury; inflammatory diseases of the Central nervous system, inflammatory bowel disease; resistance to Ann is Lin; of HIV infection; cancer; chronic obstructive pulmonary disease (COPD) or asthma.

In one embodiment, the implementation of the said treatment is the treatment of osteoarthritis, ulcerative colitis, Crohn's disease, multiple sclerosis or degenerative loss of cartilage.

In one embodiment, the implementation of the said treatment is the treatment of inflammation.

In one embodiment, the implementation of the said treatment is the treatment of rheumatoid arthritis.

In one embodiment, the implementation of the said treatment is the treatment of psoriasis.

Another aspect of the present invention relates to a method of inhibiting TACE in a cell in vitro or in vivo, which comprises effecting contact of the specified cell with an effective amount of a derivative BCSA described in this application.

Another aspect of the present invention relates to a method of regulating (e.g., inhibition) release in the cell cytokines (e.g., release of TNF-α), in vitro or in vivo, which includes the conversion of the specified cell in contact with an effective amount of a derivative BCSA described in this application.

Another aspect of the present invention refers to a kit that contains: (a) derived BCSA described in this application, preferably in the form of pharmaceutical composition and in a suitable container and/or with suitable packaging; and (b) instructions for use, for example, written instructions on how to take the derivative/composition.

Another aspect of the present invention refers to compounds that can be obtained is described in the present application is a method of synthesis or method, including those described in this application, the method of synthesis.

Another aspect of the present invention relates to compounds obtained by means described in the present application is the synthesis method or a method that involves described in the present application is the method of synthesis.

Another aspect of the present invention relates to new intermediate compounds described in this application, suitable for use in the methods of synthesis described in this application.

Another aspect of the present invention relates to the use of such new intermediate compounds described in this application, suitable for use in the methods of synthesis described in this application.

The person skilled in the art will take into account that the particular and preferred options for implementation of one aspect of the invention will also apply to other aspects of the invention.

DETAILED description of the INVENTION

Connection

One aspect of the present invention relates to compounds of the following formula and their pharmaceutically acceptable salts, hydrates and with whom LatAm (which are collectively referred to in this application as "compounds (BCSA) bicycloalkyl acid:

where:

W independently represents-N= or-CRPW=;

X independently represents-N= or-CRPX=;

Y independently represents-N= or-CRPY=;

Z independently represents-N= or-CRPZ=;

each of RPW, -RPX, -RPYand RPZif present, independently represents-H or-RRS1;

where each RRS1if present, independently represents a Deputy in the ring;

and where z is 0 or 1;

and where J< independently represents-N< or -- CH<;

and where:

-RAK- independently represents:

covalent bond,

-RAK1-, -RAK2-, -RAK3-,

-RAK4-, -RAK1-RAK4-, -RAK4-RAK1-, -RAK1-RAK4-RAK1-,

-RAK5-, -RAK1-RAK5-, -RAK5-RAK1-or-RAK1-RAK5-RAK1-.

where:

each RAK1- independently represents a saturated aliphatic C1-6alkylene, which may have substituents;

-RAK2- independently represents an aliphatic C2-6albaniles, which may have substituents;

-RAK3- independently represents an aliphatic C2-6akinyan, which may have substituents;

each RAK4- independently represents a saturated3-6cycloalkyl, which may have substituents and

each RAK5- independently represents a C3-6cycloalkenyl, which may have substituents;

and where:

-RNindependently represents-H, -RNN, -RNNNor-LN-RNNN; where:

-LN- independently represents a saturated aliphatic C1-6alkylene, which may have substituents;

-RNNNindependently represents a C1-6alkyl which may have substituents

and

-RNNNindependently represents a C3-6cycloalkyl,3-7heterocyclyl,6-10carbaryl or5-10heteroaryl, which may have substituents.

Stereochemistry

Many of the above in the present description of chemical structures shown in one or more different stereoisomeric configurations. Similarly, many shown in the present description the chemical structures of their stereocamera configuration is not shown. Similarly, many described in this application structures shown a specific stereoisomeric configuration at one or more positions, but they are not shown in one or more other positions. If the information provided in this application the chemical structure of stereoisomeric configuration at a certain position of this structure is not shown, it is understood that this image is Agen structure covers all possible stereoisomeric configuration at this position, how exactly to this configuration, and as if each stereoisomeric configuration, as well as a mixture of stereoisomers (i.e. racemic mixture) of this provision were mentioned individually.

Note that the carbon atom in the ring attached to the group J (i.e. the atom marked with an asterisk (*) in the following formula) necessarily chiral center.

In one embodiment, the implementation of the carbon atom in the ring attached to the group J (i.e. the atom marked with an asterisk (*)) has the configuration described by the following formula:

In one embodiment, the implementation of the carbon atom in the ring attached to the group J (i.e. the atom marked with an asterisk (*)) has the configuration described by the following formula:

In one embodiment, the implementation of the carbon atom in the ring attached to the group J (i.e. the atom marked with an asterisk (*)) is (R) configuration.

In one embodiment, the implementation of the carbon atom in the ring attached to the group J (i.e. the atom marked with an asterisk (*)) is in (S) configuration.

Groups W, X, Y and Z

In one embodiment, the implementation of:

W independently represents-N= or-CRPW=,

X independently represents-N= or-CRPX=,

Y independently ol dstanley a-N= or-CR PY= and

Z independently represents-N= or-CRPZ=;

and only one or only two of W, X, Y and Z are-N=.

In one embodiment, the implementation of:

W independently represents-N= or-CRPW=,

X independently represents-N= or-CRPX=,

Y independently represents-N= or-CRPY=, and

Z independently represents-N= or-CRPZ=;

and only one group of W, X, Y and Z represents-N=.

In one embodiment, the implementation of:

W independently represents-CRPW=,

X independently represents-CRPX=,

Y independently represents-CRPY= and

Z independently represents-CRPZ=

In one embodiment, the implementation of:

W independently represents-N=,

X independently represents-CRPX=,

Y independently represents-CRPY= and

Z independently represents-CRPZ=.

In one embodiment, the implementation of:

W independently represents-CRPW=,

X independently represents-N=,

Y independently represents-CRPY= and

Z independently represents-CRPZ=.

In one embodiment, the implementation of:

W independently represents-CRPW=

X independently represents-CRPX=,

Y independently represents-N= and

Z independently presented yet a-CR PZ=.

In one embodiment, the implementation of:

W independently represents-CRPW=,

X independently represents-CRPX=,

Y independently represents-CRPY= and

Z independently represents-N=.

In one implementation, each of RPW, -RPX, -RPYand RPZif present, independently represents-N.

Group[NH]z-

In one embodiment, the realization of z is independently 1.

In one embodiment, the realization of z is independently equal to 0.

Group J

In one embodiment, the implementation-J< independently represents-N<.

In one embodiment, the implementation-J< independently represents-CH<.

The group-RAK-

In one embodiment, the implement-RAK- independently is a covalent bond,

-RAK1-, -RAK2-, -RAK3-

-RAK4-, -RAK1-RAK4-, -RAK4-RAK1-, -RAK1-RAK4-RAK1-,

-RAK5-, -RAK1-RAK5-, -RAK5-RAK1-, -RAK1-RAK5-RAK1-.

In one embodiment, the implement-RAK- independently represents:

-RAK1, -RAK2-, -RAK3-

-RAK4-, -RAK1-RAK4-, -RAK4-RAK1-, -RAK1-RAK4-RAK1-,

-RAK5-, -RAK1-RAK5-, -RAK5-RAK1-, -RAK1-RAK5-RAK1-.

In one embodiment, the implement-R AK- is independently:

-RAK1-, -RAK2-, -RAK3-,

-RAK4-, -RAK1-RAK4-, -RAK4-RAK1-, -RAK1-RAK4-RAK1-.

In one embodiment, the implement-RAK- independently represents-RAK1-, -RAK2or RAK3-.

In one embodiment, the implement-RAK- independently represents-RAK1or RAK2-.

In one embodiment, the implement-RAK- independently represents-RAK1-.

In one embodiment, the implement-RAK- independently represents-RAK2-.

In one embodiment, the implement-RAK- independently represents-RAK3-.

In one embodiment, the implement-RAK- independently represents-RAK1- or a covalent bond.

In one embodiment, the implement-RAK- independently represents a covalent bond.

In one embodiment, the implement-RAK- independently represents:

-RAK4-, -RAK1-RAK4-, -RAK4-RAK1or RAK1-RAK4-RAK1-.

In one embodiment, the implement-RAK- independently represents-RAK4-.

In one embodiment, the implement-RAK- independently represents-RAK1-RAK4-.

In one embodiment, the implement-RAK- independently represents-RAK4-RAK1-.

In one embodiment, the implementation is AI-R AK- independently represents a

-RAK1-RAK4-RAK1-.

The group-RAK1-

In one implementation, each of RAK1-if present, independently represents a saturated aliphatic C1-6alkylene, which may have substituents.

In one implementation, each of RAK1-if present, independently represents a saturated aliphatic C1-4alkylene, which may have substituents.

In one implementation, each of RAK1-if present, may independently do not have or have substituents, for example one or more substituent (for example, 1, 2, 3) -RG1.

In one implementation, each of RAK1-if it is present, the substituents independently are absent.

In one implementation, each of RAK1-if present, independently represents -(CH2)q-where q is independently 1, 2, 3, 4, 5 or 6.

In one implementation, each of RAK1-if present, independently represents -(CH2)-, -(CH2)2-, -(CH2)3- or -(CH2)4-.

In one implementation, each of RAK1-if present, independently represents -(CH2)-, -(CH2)2- or -(CH2)3-.

In one implementation, each of RAK1-if p is outstay, independently represents -(CH2)- or -(CH2)2-.

In one implementation, each of RAK1-if present, independently represents -(CH2)-.

The group-RAK2-

In one implementation, -RAK2-if present, independently represents an aliphatic C2-6albaniles, which may have substituents.

The term "C2-6albaniles"used in this application, refers to a divalent bidentate aliphatic hidrocarburos group that contains from 2 to 6 carbon atoms and has at least one carbon-carbon bond, but does not have a triple carbon-carbon bonds.

In one implementation, -RAK2-if present, independently represents an aliphatic C2-4albaniles, which may have substituents.

In one implementation, -RAK2-, if present, is independently may not have or may have substituents, for example one or more Deputy, for example, one or more (e.g. 1, 2, 3) Deputy-RG1.

In one implementation, -RAK2-, if present, is independently does not have a Deputy.

In one implementation, -RAK2-if present, independently represents:

-CH=CH-,

- (CH3)=CH-, -CH=C(CH3)-,

-CH=CH-CH2-,

- (CH3=CH-CH 2-, -CH=C(CH3)-CH2-, -CH=CH-CH(CH3)-,

-CH2-CH=CH-,

-CH(CH3)-CH=CH-, -CH2- (CH3)=CH-, -CH2-CH=C(CH3)-,

-CH=CH-CH2-CH2-, -CH2-CH=CH-CH2- or-CH2-CH2-CH=CH-.

The group-RAK3-

In one implementation, -RAK3-if present, independently represents an aliphatic C2-6akinyan, which may have substituents.

The term "C2-6akinyan"used in the present description, refers to a divalent bidentate aliphatic hidrocarburos group, which contains at least one carbon-carbon triple bond and perhaps also one or more double carbon-carbon connection.

In one implementation, -RAK3-if present, independently represents an aliphatic C2-4akinyan, which may have substituents.

In one implementation, the group-RAK3-, if present, is independently no or substituents, for example one or more Deputy, for example, one or more (e.g. 1, 2, 3) Deputy-RG1.

In one implementation, -RAK3-, if present, is independently does not have a Deputy.

In one implementation, -RAK3-if present, independently represents:

-C≡C-,

-C≡C-CH2-, -C≡is-CH(CH 3)-,

-CH2-C≡C-, -CH(CH3)-C≡C-,

-C≡C-CH2-CH2-, -C≡C-CH(CH3)-CH2-, -C≡C-CH2-CH(CH3)-,

-CH2-C≡C-CH2-, -CH(CH3)-C≡C-CH2-, -CH2-C≡C-CH(CH3)-,

-CH2-CH2-C≡C-, -CH(CH3)-CH2-C≡C-, -CH2-CH(CH3)-C≡C-,

-C≡C-CH=CH-, -C≡C-C(CH3)=CH-, -C≡C-CH=C(CH3)-,

-CH=CH-C≡C-, -C(CH3)=CH-C≡C - or-CH=C(CH3)-C≡C-.

Group-RAK4-, -RAK1-RAK4-, -RAK4-RAK1and RAK1-RAK4-RAK1-

In one implementation, each of RAK4-if present, independently represents a saturated3-6cycloalkyl, which may have substituents.

The term "saturated With3-6cycloalkyl"used in this application, refers to a divalent bidentate saturated carbocyclic group which contains in the ring from 3 to 6 atoms, and these atoms of the ring are carbon atoms, and where one or two ring atoms are connection points.

In one implementation, each of RAK4-if present, independently represents a saturated3-5cycloalkyl, which may have substituents.

In one implementation, each of RAK4-if present, independently represents n is sydeny and possibly replaced With 3-4cycloalkyl, which may have substituents.

In one implementation, each of RAK4-if present, independently represents a saturated and possibly replaced With4-6cycloalkyl, which may have substituents.

In one implementation, each of RAK4-if present, independently represents a saturated and possibly replaced With5-6cycloalkyl, which may have substituents.

In one implementation, each of RAK4-, if present, is independently may not have or may have substituents, for example one or more Deputy, for example, one or more (e.g. 1, 2, 3) Deputy-RG1.

In one implementation, each of RAK4-, if present, is independently does not have a Deputy.

In one implementation, each of RAK4-if present, independently represents:

cyclopropyl-diyl, cyclobutyl-diyl, cyclopentyl-diyl or cyclohexyl-diyl.

In one implementation, each of RAK4-if present, independently represents cyclopropyl-diyl.

In one implementation, each of RAK4-if present, independently represents cyclopropyl-1,1-diyl.

In one implementation, each of RAK1-RAK4-if present, independently represents:

METI encyclopae-diyl, methylenecyclobutane-diyl, methylenecyclobutane-diyl or methylenechloride-diyl.

In one implementation, each of RAK4-RAK1-if present, independently represents:

cyclopropyl-diyl-methylene cyclobutyl-dial-methylene,

cyclopentyl-dial-methylene or cyclohexyl-diyl-methylene.

In one implementation, -RAK1-RAK4-RAK1-if present, independently represents:

methylene-cyclopropyl-diyl-methylene, methylene-cyclobutyl-dial-methylene,

methylene-cyclopentyl-dial-methylene or methylene-cyclohexyl-diyl-methylene.

The group-RAK5-

In one implementation, each of RAK5-if present, independently represents a C3-6cycloalkenyl, which may have substituents.

The term "C3-6cycloalkenyl"used in this application, refers to a divalent bidentate carbocyclic group which contains in the ring from 3 to 6 atoms, and the ring at least one carbon-carbon double bond, but not in the ring triple carbon-carbon link, and these ring atoms are carbon atoms, and one or two of these atom rings are connection points.

In one implementation, each of RAK5-if present, independently represents a C3-5qi is leukeran, which may have substituents.

In one implementation, each of RAK5-if present, independently represents a C3-4cycloalkenyl, which may have substituents.

In one implementation, each of RAK5-if present, independently represents a C4-6cycloalkenyl, which may have substituents.

In one implementation, each of RAK5-if present, independently represents a C5-6cycloalkenyl, which may have substituents.

In one implementation, each of RAK5-, if present, is independently may not have or may have substituents, for example one or more Deputy, for example, one or more (e.g. 1, 2, 3) Deputy-RG1.

In one implementation, each of RAK5-, if present, is independently does not have a Deputy.

In one implementation, each of RAK5-if present, independently represents:

cyclopropyl-diyl, CYCLOBUTANE-diyl, cyclopentane-diyl or cyclohexane-diyl.

In one implementation, each of RAK1-RAK5-if present, independently represents:

Methylene-cyclopropane-diyl, methylene-cyclobutenyl-diyl,

Methylene-cyclopentenyl-diyl or methylene-cyclohexenyl-diyl.

In one implementation, each of R AK5-RAK1-if present, independently represents:

cyclopropyl-diyl-methylene cyclobutenyl-dial-methylene,

cyclopentenyl-dial-methylene or cyclohexenyl-dial-methylene.

In one implementation, -RAK1-RAK5-RAK1-if present, independently represents:

methylene-cyclopropane-dial-methylene, methylene-cyclobutenyl-dial-methylene,

methylene-cyclopentenyl-dial-methylene or methylene-cyclohexenyl-dial-methylene.

Deputy-RG1

In one implementation, each of RG1if present, independently represents-F, -Cl, -Br, -I, -OH, -ORA1, -OCF3-C(=O)HE, -C(=O)ORA1, -NH2-The otherA1, -NRA12, -NRA2RA3, -C(=O)-NH2, -C(=O)-otherA1, -C(=O)-NRA12, -C(=O)-NRA2RA3, phenyl or benzyl; wherein each radical RA1independently represents an alkyl, phenyl or benzyl; each-NRA2RA3independently represents pyrrolidino-, piperidino, piperazino or morpholino group which may have or have substituents selected from C1-3the alkyl and-CF3.

In one implementation, each of RG1if present, independently represents-F, -Cl, -Br, -I, -OH, -OMe, -OEt or-OCF3.

The group-RN

In one embodiment, the implement-RNregardless of performance, is to place a-H, -RNN, -RNNor-LN-RNNN.

In one implementation, -RNindependently represents-H, -RNNNor

-LN-RNNN.

In one implementation, -RNindependently represents-H or-RNN.

In one implementation, -RNindependently represents-RNNNor-LN-RNNN.

In one implementation, -RNindependently represents-N.

In one implementation, -RNindependently represents-RNN.

In one implementation, -RNindependently represents-RNNN.

In one implementation, -RNindependently represents-LN-RNNN.

Group-LN-

In one embodiment, the implementation of LN-if present, independently represents a saturated aliphatic C1-6alkylene, which may have substituents.

In one implementation, -LN-if present, independently represents a saturated aliphatic C1-3alkylene, which may have substituents.

In one embodiment, the implementation of LN-, if present, is independently may not have or may have substituents, for example one or more Deputy, for example, one or more (e.g. 1, 2, 3) Deputy-RG2.

In one implementation, -LN -, if present, is independently has no deputies.

In one implementation, -LN-if present, independently represents-CH2-, -CH2CH2- or-CH2CH2CH2-.

In one implementation, -LN-if present, independently represents-CH2- or-CH2CH2-.

In one implementation, -LN-if present, independently represents-CH2-.

Deputy-RG2

In one implementation, each of RG2if present, independently represents-F, -Cl, -Br, -I, -OH, -ORA1, -OCF3-C(=O)HE, -C(=O)ORA1,

-NH2-The otherA1,, -NRA2RA3, -C(=O)-NH2, -C(=O)-otherA1,, -C(=O)-NRA2RA3, phenyl, or benzyl; where each RA1independently represents an alkyl, phenyl or benzyl; each-NRA2RA3independently represents pyrrolidino-, piperidino, piperazino or morpholinopropan and independently may not have or may have as a substituent one or more group selected from C1-3the alkyl and-CF3.

In one implementation, each of RG2if present, independently represents-F, -Cl, -Br, -I, -OH, -OMe, -OEt or-OCF3.

The group-RNN

In one implementation, -R NNif present, independently represents a C1-6alkyl which may have substituents.

In one implementation, -RNNif present, independently represents a C1-4alkyl which may have substituents.

In one implementation, -RNNif present, independently no or substituents, for example one or more Deputy, for example, one or more (e.g. 1, 2, 3) Deputy-RG3.

In one implementation, -RNNif present, independently has no deputies.

In one implementation, -RNNif present, independently represents-Me, -Et, -n-Pr or I-Pr.

Deputy-RG3

In one implementation, each of RG3if present, independently represents-F, -Cl, -Br, -I, -OH, -ORA1, -OCF3-C(=O)HE, -C(=O)ORA1,

-NH2-The otherA1,, -NRA2RA3, -C(=O)-NH2, -C(=O)-otherA1,, -C(=O)-NRA2RA3; where each RA1independently represents a C1-4alkyl, phenyl or benzyl; each-NRA2RA3independently represents pyrrolidino-, piperidino, piperazino or morpholinopropan and independently may not have or may have as substituents one or more group that is selected from the 1-3the alkyl and-CF3.

In one implementation, each of RG3if present, independently represents-F, -Cl, -Br, -I, -OH, -OMe, -OEt or-OCF3.

The group-RNNN

In one implementation, -RNNNif present, independently represents a C3-6cycloalkyl,3-7heterocyclyl,6-10carbaryl or5-10heteroaryl, which may have substituents.

In one implementation, -RNNNif present, independently represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, imidazolidinyl, pyrazolidine, piperidine, piperizine, morpholine, thiomorpholine, azepine, diazepine, phenyl, naphthyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzofuranyl, isobenzofuranyl, indazoles, purinol, chinoline, ethenolysis, naphthyridine, honokalani, hintline, indolinyl, indolyl, isoindolyl, carbazolyl, carbolines, acridines, phenoxazine or phenothiazinyl that may have substituents.

In one implementation, -RNNNif present, independently represents a C6-10carbaryl or5-10heteroaryl, which may have substituents.

In one implementation, -RNNNif present, independently represents a phenyl, naphthyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzofuranyl, isobenzofuranyl, indazoles, purinol, chinoline, ethenolysis, naphthyridine, honokalani, hintline, indolinyl, indolyl, isoindolyl, carbazolyl, carbolines, acridines, phenoxazine or phenothiazinyl, which may have substituents.

In one implementation, -RNNNif present, independently represents a phenyl, naphthyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, which may have substituents.

In one implementation, -RNNNif present, independently represents a phenyl, naphthyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl or pyrazolyl, which may have substituents.

In one implementation, -RNNNif present, independently represents a possibly substituted phenyl, naphthyl, pyridyl or pyrazolyl, which may have substituents.

In one implementation, -RNNNif present, independently represents a possibly substituted phenyl or naphthyl, which may have substituents.

In one the m variant of realization, -RNNNif present, independently represents a possibly substituted phenyl, which may have a Deputy.

In one implementation, -RNNNif present, independently may not have or may have substituents, for example, not to have or to have one or more (e.g. 1, 2, 3) the Deputy.

In one implementation, -RNNNif present, independently represents phenyl, which may have a substituent in paraprotein and to be filled for all other provisions.

In one implementation, each Deputy u-RNNNif present, independently represents-RS.

In one implementation, -RNNNif present, independently does not have a Deputy.

Deputy-RRS1

In one implementation, each of RRS1if present, independently represents the same group as defined for RS.

In one implementation, each of RRS1if present, independently represents-F, -Cl, -Br, -I, -RA1, -CF3, -OH, -ORA1, -OCF3-C(=O)HE, -C(=O)ORA1, -NH2-The otherA1,, -NRA2RA3, -C(=O)-NH2, -C(=O)-otherA1,, -C(=O)-NRA2RA3, phenyl or benzyl; where each RA1independently represents a C1-4alkyl,phenyl or benzyl; and each-NRA2RA3independently represents pyrrolidino-, piperidino, piperazino or morpholinopropan, independently unsubstituted or substituted by one or more groups selected from C1-3the alkyl and-CF3; and optionally two adjacent groups RRS1if present, may form-OCH2O-, -OCH2CH2O -, or-OCH2CH2CH2O - group.

In one implementation, each of RRS1if present, independently represents-F, -Cl, -Br, -I, -Me, -Et, -CF3, -OH, -OMe, -OEt, -OCF3or phenyl; and additionally, two adjacent groups RRS1if present, may form-OCH2CH2O-.

In one implementation, each of RRS1if present, is an independently-F, -Cl, -Br, -Me, -CF3, -OMe, -OEt or phenyl, and optionally two adjacent groups RRS1if present, may form-OCH2CH2O-.

Deputy-RS

In one implementation, each of RSif present, independently represents:

-F, -Cl, -Br, -I,

-RD1,

-CF3, -CH2CF3, -CF2CF2H,

HE

-L1-OH,

-O-L1-OH,

-ORD1,

-L1-ORD1,

-O-L1-ORD1,

-OCF3, -OCH2CF3, -OCF2CF2H,

-SH

-SRD1, -SCF3,

-C

-NO2,

-NH2-The otherD1, -NRD12, -NRN1RN2,

-L1-NH2, -L1-OtherD1, -L1-NRD12, -L1-NRN1RN2,

-O-L1-NH2, -O-L1-OtherD1, -O-L1-NRD12, -O-L1-NRN1RN2,

-NH-L1-NH2, -NH-L1-OtherD1, -NH-L1-NRD12, -NH-L1-NRN1RN2,

-NRD1-L1-NH2, -NRD1-L1-OtherD1, -NRD1-L1-NRD12, -NRD1-L1-NRN1RN2,

-C(=O) - OH,

-C(=O)ORD1,

-C(=O)NH2, -C(=O)otherD1, -C(=O)NRD12, -C(=O)NRN1RN2,

-NHC(=O)RD1, -NRD1C(=O)RD1,

-NHC(=O)ORD1, -NRD1C(=O)ORD1,

-OC(=O)NH2, -OC(=O)otherD1, -OC(=O)NRD12, -OC(=O)NRN1RN2,

-OC(=O)RD1,

-C(=O)RD1,

-NHC(=O)NH2, -NHC(=O)otherD1, -NHC(=O)NRD12, -NHC(=O)NRN1RN2,

-NRD1C(=O)NH2, -NRD1C(=O)otherD1, -NRD1C(=O)NRD12, -NRD1C(=O)NRN1RN2,

-NHS(=O)2RD1, -NRD1S(=O)2RD1,

-S(=O)2NH2, -S(=O)2OtherD1, -S(=O)2NRD12, -S(=O)2NRN1RN2,

-S(=O)RD1,

-S(=O)2RD1,

-OS(=O)2RD1,

-S(=O)2ORD1,

=O,

=NRD1,/p>

=NOH, or

=NORD1

and additionally two closely spaced to the group ring RSif present, together can form a group-O-L2-O-;

where:

each-L1- independently represents a saturated aliphatic C1-5alkylen, aliphatic C2-5albaniles or aliphatic C2-5akinyan;

each-L2- independently represents a saturated aliphatic C1-3alkylen;

each of the groups-NRN1RN2, -RN1and RN2together with the nitrogen atom to which it is attached, forms a 5-, 6 - or 7-membered nonaromatic ring, which has only 1 heteroatom in the ring or only 2 heteroatoms in the ring, and one of the only two heteroatoms in the ring represents N and the other of these two heteroatoms in the ring independently represents N, O or S;

each RD1independently represents:

-RE1, -RE2, -RE3, -RE4, -RE5, -RE6, -RE7, -RE8,

-L3-RE4, -L3-RE5, -L3-RE6, -L3-RE7or-L3-RE8;

where:

each RE1independently represents a saturated aliphatic C1-6alkyl;

each RE2independently represents an aliphatic C2-6alkenyl;

each Rsup> E3independently represents an aliphatic C2-6quinil;

each RE4independently represents a saturated3-6cycloalkyl;

each RE5independently represents a C3-7cycloalkenyl;

each RE6independently represents a non-aromatic C3-7heterocyclyl;

each RE7independently represents a C6-14carbaryl;

each RE8independently represents a C5-14heteroaryl;

each-L3- independently represents a saturated aliphatic C1-3alkylen;

and where:

each C1-6alkyl, C2-6alkenyl,2-6quinil,3-6cycloalkyl,3-6cycloalkenyl, nah3-7heterocyclyl, C6-14carbaryl,5-14heteroaryl and C1-3alkylene may have a Deputy, for example, one or more (e.g. 1, 2, 3) Deputy-RG4where each RG4independently represents:

-F, -Cl, -Br, -I,

-RF1,

-CF3, -CH2CF3, -CF2CF2H-HE,

-L4-OH,

-O-L4-OH,

-ORF1,

-L4-ORF1,

-O-L4-ORF1,

-OCF3, -OCH2CF3, -OCF2CF2H,

-SH

-SRF1, -SCF3,

-CN

-NO2,

-NH2-The otherF1, -NRF12, -NRN3RN4,

-L4 -NH2, -L4-OtherF1, -L4-NRF12or-L4-NRN3RN4,

-O-L4-NH2, -O-L4-OtherF1, -O-L4-NRF12, -O-L4-NRN3RN4,

-NH-L4-NH2, -NH-L4-OtherF1, -NH-L4-NRF12, -NH-L4-NRN3RN4,

-NRF1-L4-NH2, -NRF1-L4-OtherF1, -NRF1-L4-NRF12, -NRF1-L4-NRN3RN4,

-C(=O) - OH,

-C(=O)ORF1,

-C(=O)NH2, -C(=O)otherF1, -C(=O)NRF12or-C(=O)NRN3RN4;

where:

each RF1independently represents a saturated aliphatic C1-4alkyl, phenyl or benzyl;

each-L4- independently represents a saturated aliphatic C1-5alkylen and

each group-NRN3RN4, -RN3and RN4together with the nitrogen atom to which it is attached, forms a 5-, 6 - or 7-membered non-aromatic ring having 1 heteroatom in the ring or only 2 heteroatoms as ring, and one of these only two heteroatoms in the ring represents N and the other of these two heteroatoms in the ring independently represents N, O or S.

In one implementation, each of RSif present, independently represents:

-F, -Cl, -Br, -I,

-RD ,

-CF3, -CH2CF3, -CF2CF2H,

HE

-L1HE

-O-L1-OH,

-ORD1,

-L1-ORD1,

-O-L1-ORD1,

-OCF3, -OCH2CF3, -OCF2CF2H,

-SH

-SRD1, -SCF3,

-CN

-NO2,

-NH2-The otherD1, -NRD12, -NRN1RN2,

-L1-NH2, -L1-OtherD1, -L1-NRD12, -L1-NRN1RN2,

-O-L1-NH2, -O-L1-OtherD1, -O-L1-NRD12, -O-L1-NRN1RN2,

-NH-L1-NH2, -NH-L1-OtherD1, -NH-L1-NRD12, -NH-L1-NRN1RN2,

-NRD1-L1-NH2, -NRD1-L1-OtherD1, -NRD1-L1-NRD12, -NRD1-L1-NRN1RN2,

-C(=O) - OH,

-C(=O)ORD1,

-C(=O)NH2, -C(=O)otherD1, -C(=O)NRD12, -C(=O)NRN1RN2,

-NHC(=O)RD1, -NRD1C(=O)RD1,

-OC(=O)RD1,

-C(=O)RD1,

-NHS(=O)2RD1, -NRD1S(=O)2RD1,

-S(=O)2NH2, -S(=O)2OtherD1, -S(=O)2NRD12or-S(=O)2NRN1RN2;

and additionally, two adjacent to the ring group-RSif present may together form a group-O-L2-O-.

In one implementation, each is-R Sif present, independently represents-ORD1.

In one implementation, each group-NRN1RN2if present, independently represents pyrrolidino-, imidazolidine-, pyrazolidine-, piperidino, piperazino, morpholino, thiomorpholine-, azepino or diazepinone and independently may not have or may have substituents, for example one or more (e.g. 1, 2, 3) group, which is selected from C1-3the alkyl and-CF3.

In one implementation, each group-NRN1RN2if present, independently represents pyrrolidino-, piperidino, piperazino or morpholinopropan and independently may not have or may have substituents, for example one or more (e.g. 1, 2, 3) group, which is selected from C1-3the alkyl and-CF3.

In one implementation, each of RD1if present, independently represents:

-RE1, -RE3, -RE4, -RE7, -RE8,

-L3-RE4, -L3-RE7or-L3-RE8.

In one implementation, each radical RD1if present, independently represents:

-RE1, -RE3, -RE7, -RE8, -L3-RE7or-L3-RE8.

In one implementation, each of RD1if present, independently represents-L3-R E7or-L3-RE8.

In one implementation, each of RD1if present, independently represents-RE3.

In one implementation, each of RE1if present, independently represents methyl, ethyl, n-propyl, ISO-propyl, n-butyl, ISO-butyl, sec-butyl or tert-butyl, which may have substituents.

In one implementation, each of RE2if present, independently represents an aliphatic C2-4alkenyl, which may have substituents.

In one implementation, each of RE2if present, independently represents-CH2-CH=CH2which may have substituents.

In one implementation, each of RE3if present, independently represents an aliphatic C3-5quinil, which may have substituents.

In one implementation, each of RE3if present, independently represents-CH2-C≡CH, -CH(CH3)-C≡CH, -CH2-C≡C-CH3, -CH(CH3)-C≡C-CH3, -CH2-C≡C-CH2-CH3or-CH2-CH2-C≡CH, which may have substituents.

In one implementation, each of RE4if present, independently represents a possibly substituted cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, which may have substituents.

In one implementation, each of RE6if present, independently represents azetidine, pyrrolidine, imidazolidine, pyrazolidine, piperidinyl, piperazinil, morpholinyl, azepine, diazepine, tetrahydrofuranyl, tetrahydropyranyl, dioxane, which may have substituents.

In one implementation, each of RE6if present, independently represents pyrrolidinyl, piperidinyl, piperazinil, morpholinyl, tetrahydrofuranyl or tetrahydropyranyl, which may have substituents.

In one implementation, each of RE7if present, independently represents phenyl or naphthyl, which may have substituents.

In one implementation, each of RE7if present, independently represents a possibly substituted phenyl, which may have substituents.

In one implementation, each of RE8if present, independently represents furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzofuranyl, isobenzofuranyl, indazoles, purinol, chinoline, ethenolysis, naphthyridine, honokalani, hintline, indolinyl, indolyl, isoindolyl, carbazolyl, carbolines, acridines, phenoxazine or phenothiazines is l, which may have substituents.

In one implementation, each of RE8if present, independently represents furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, chinoline or ethenolysis, which may have substituents.

In one implementation, each of RE8if present, independently represents furanyl, pyrrolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, pyridyl, chinoline or ethenolysis, which may have substituents.

In one implementation, each-L1-if present, independently represents a saturated aliphatic C1-5alkylen or aliphatic C2-5akinyan.

In one implementation, each-L1-if present, independently represents a saturated aliphatic C1-5alkylen.

In one implementation, each-L1-if present, independently represents a saturated aliphatic C2-5alkylen.

In one implementation, each-L2-if present, independently represents-CH2- or-CH2CH2-

In one implementation, each-L2-if present, represents n is dependent-CH 2CH2-

In one implementation, each-L3-if present, independently represents-CH2-.

In one implementation, each of RG4if present, independently selected from:

-F, -Cl, -Br, -I,

-RF1,

-CF3, -CH2CF3, -CF2CF2H,

HE

-L4-OH,

-O-L4-OH,

-ORF1,

-L4-ORF1,

-O-L4-ORF1,

-OCF3, -OCH2CF3, -OCF2CF2H,

-SRF1,

-NH2-The otherF1, -NRF12, -NRN3RN4,

-L4-NH2, -L4-OtherF1, -L4-NRF12or-L4-NRN3RN4,

-O-L4-NH2, -O-L4-OtherF1, -O-L4-NRF12, -O-L4-NRN3RN4,

-NH-L4-NH2, -NH-L4-OtherF1, -NH-L4-NRF12, -NH-L4-NRN3RN4,

-NRF1-L4-NH2, -NRF1-L4-OtherF1, -NRF1-L4-NRF12or-NRF1-L4-NRN3RN4.

In one implementation, each of RG4if present, independently selected

from:

-F, -Cl, -Br, -I,

-RF1,

HE

-ORF1,

-NH2-The otherF1, -NRF12and-NRN3RN4.

In one implementation, each group-NRN3RN4if present, is independently researched the Simo is pyrrolidino-, imidazolidine-, pyrazolidine-, piperidino, piperazino, morpholino, thiomorpholine-, azepino or diazepino, which independently may not have or may have as substituents for example, one or more (e.g. 1, 2, 3) group, which is selected from C1-3the alkyl and-CF3.

In one implementation, each group-NRN3RN4if present, independently represents pyrrolidino-, piperidino, piperazino or morpholinopropan, which independently may not have or may have substituents, for example one or more (e.g. 1, 2, 3) group, which is selected from C1-3the alkyl and-CF3.

In one implementation, each of RF1if present, independently represents a saturated aliphatic C1-4alkyl.

In one implementation, each-L4-if present, independently represents a saturated aliphatic C2-5alkylen.

Some preferred combinations

In one preferred implementation:

W independently represents-CRPW=;

X independently represents-CRPX=;

Y independently represents-CRPY=;

Z independently represents-CRPZ=;

each of the groups RPW, -RPX, -RPYand RPZif present, independently represents-H or-RRS1 ;

z is 1;

-J< independently represents-N<;

-RAK- independently represents-RAK1-;

-RAK1- independently represents-CH2and

-RNindependently represents-RNNN.

In one preferred implementation, in addition, each group

-RRS1if present, independently represents-F, -Cl, -Br, -I, -Me, -Et, -CF3,

-OH, -OMe, -OEt, -OCF3or phenyl; and additionally, two adjacent groups RRS1if present, may form-OCH2CH2O-.

In one preferred implementation, in addition, each group

-RNNNindependently represents phenyl which may have substituents, for example one or more (e.g. 1, 2, 3) Deputy-RS.

In one preferred implementation, additionally, -RNNNindependently represents a phenyl, which may have a substituent in paraprotein, such as Deputy-RS; and be unsubstituted in all other positions.

In one preferred implementation, in addition, RNNNindependently represents a phenyl, which may have as a substituent-RSwhere-RSindependently represents-ORD1.

In one preferred implementation, in addition, RNNN independently represents a phenyl, possibly substituted in paraprotein Deputy-RSand unsubstituted in all other positions, where-RSindependently represents-ORD1.

In one preferred implementation, in addition, RNNNindependently represents a phenyl, which may have as a substituent-RSwhere-RSindependently represents-ORD1where-RD1independently represents-L3-RE7or-L3-RE8where-L3- independently represents-CH2-.

In one preferred implementation, in addition, RNNNindependently represents a phenyl, which may have as a substituent paraprotein group-RSand not to have deputies in all other positions, where-RSindependently represents-ORD1where-RD1independently represents-L3-RE7or-L3-RE8where-L3- independently represents-CH2-.

In one preferred implementation, in addition, RNNNindependently represents a phenyl, which may have as a substituent-RSwhere-RSindependently represents-ORD1where-RD1independently represents-RE3.

In one preferred options the ante implementation, additionally, RNNNindependently represents a phenyl, which may have as a substituent paraprotein Deputy-RSand to be unsubstituted in all other positions, where-RSindependently represents-ORD1where-RD1independently represents-RE3.

Molecular mass

In one implementation, the connection - derived BCSA has a molecular weight of from 227 to 1200.

In one implementation, the lower bound of the range is 240, 250, 275, 300 or 350.

In one implementation, the upper limit of the range is 1100, 1000, 900, 800, 700 or 600.

In one implementation, the range is from 240 to 600.

Combination

All compatible combinations of the above variants of realization unambiguously disclosed in the present description, as if each and every combination was individually and explicitly described.

Examples of specific implementation options

In one implementation of the present invention compounds selected from compounds of the following formula and pharmaceutically acceptable salt, hydrate and solvate of such compounds:

Identification numberThe connection numberStructure
IX-0015.1
IX-002(+)-(S)-5.1

Identification numberThe connection numberStructure
IX-003(-)-(R)-5.1
IX-0045.2
IX-0055.3
IX-0065.4
IX-0075.5

Identification numberThe connection numberStructure
IX-0085.6
IX-0095.7
IX-0105.8
IX-0115.9
IX-0125.10

Identification numberThe connection numberStructure
IX-0135.11
IX-0145.12
IX-0155.13
IX-0165.14
IX-0175.15

Identification numberThe connection numberStructure
IX-0185.16
IX-0195.17
IX-0205.18
IX-0215.19
IX-0225.20
IX-0235.21

Identification numberThe connection numberStructure
IX-0245.22
IX-0255.23
IX-0265.24
IX-0275.25
IX-0285.26

Identification numberThe connection numberStructure
IX-0295.27
IX-0305.28
IX-0315.29
IX-0325.30
IX-0335.31

Identification numberThe connection numberStructure is RA
IX-0345.32
IX-0355.33
IX-0365.34
IX-0375.35
IX-0385.36

Identification numberThe connection numberStructure
IX-0395.37
IX-0405.38
IX-0415.39
IX-0425.40
IX-043/td> 5.41
IX-0445.42

Identification numberThe connection numberStructure
IX-0455.43
IX-046(+)-5.43
IX-047(-)-5.43
IX-0485.44

Identification numberThe connection numberStructure
IX-049(+)-5.44
IX-050(-)- 5.44
IX-0515.45
IX-0525.46
IX-0535.47

Identification numberThe connection numberStructure
IX-0545.48
IX-0555.49
IX-0565.50
IX-0575.51
IX-0585.52

Identification numberThe connection number Structure
IX-0595.53
IX-0605.54
IX-0615.55
IX-0625.56
IX-0635.57

Identification numberThe connection numberStructure
IX-0645.58
IX-0655.59
IX-0665.60
IX-0675.61/td>
IX-0685.62

Identification numberThe connection numberStructure
IX-0695.63
IX-0705.64
IX-0715.65
IX-0725.66
IX-0735.67
IX-0745.68

Identification numberThe connection numberStructure
IX-07524
IX-07629
IX-07736
IX-07839
IX-07943

IX-085
Identification numberThe connection numberStructure
IX-08048.1
IX-08148.2
IX-08254.1
IX-08354.2
IX-08454.3
54.4

Identification numberThe connection numberStructure
IX-08654.5
IX-08754.6
IX-08854.7
IX-08954.8
IX-09054.9
IX-09154.10

Identification numberThe connection numberStructure
IX-09254.11
IX-09354.12
IX-09457
IX-09562.1
IX-09662.2

In one implementation of the present invention compounds selected from compounds of the following formula and pharmaceutically acceptable salt, hydrate and solvate of such compounds:

Identification numberThe connection numberStructure
IX-09772

In one embodiment, the implementation of compounds selected from compounds of the following formula and their pharmaceutically acceptable salt, hydrate and solvate:

Identification numberThe connection number Structure
IX-09877

In one embodiment, the implementation of compounds selected from compounds of the following formula and pharmaceutically acceptable salt, hydrate and solvate of such compounds:

Identification numberThe connection numberStructure
IX-0994.1

Identification numberThe connection numberStructure
IX-1004.43
IX-1014.44

Additional examples

In one implementation of the present invention compounds selected from compounds of the following formula and pharmaceutically acceptable salt, hydrate and solvate of such compounds:

012
345
678
901
234
567

890
123
456

In one implementation of the present invention compounds selected from compounds of the following formula and pharmaceutically acceptable salt, hydrate and solvate of such compounds:

789
01

In one embodiment, the implementation of compounds selected from compounds n is residuum formula and pharmaceutically acceptable salts, hydrate and solvate of such compounds:

234

In one implementation of the present invention compounds selected from compounds of the following formula and pharmaceutically acceptable salt, hydrate and solvate of such compounds:

56

In one embodiment, the implementation of the compounds according to the present invention is selected from compounds of the following formula and pharmaceutically acceptable salt, hydrate and solvate of such compounds:

789
012
34

Essentially purified form.

One aspect of the present invention relates to derivatives of compounds BCSA described in this application in substantially purified form and/or in a form that is virtually pollution-free.

In one implementation, in substantially purified form is clean at least 50% by weight, for example at least 60% by weight, for example at least 70% by weight, for example at least 80% by weight, for example at least 90% by weight, for example at least 95% by weight, for example at least 97% by weight, for example at least 98% by weight, for example at least 99% by weight.

Unless expressly stated, essentially purified form refers to the connection in any stereoisomeric or enantiomeric form. For example, in one embodiment, the implementation is essentially purified form is a mixture of stereoisomers, that is purified from other compounds. In one implementation, under substantially purified form means the form relating to a single stereoisomer, for example, optically pure stereoisomer. In one implementation under essentially pure form understand the mixture of enantiomers. In one embodiment, the implement to substantially pure form include equimolar mixture of enantiomers (i.e. racemic mixture or racemate). In one implementation under substantially purified form understand a single enantiomer, for example, optically pure enantiomer.

In one implementation, the impurities are not more than 50% by weight, for example, not more than 40 mass%, for example, not more than 30 mass%, for example not more than 20 mass%, for example, not more than 10% by weight, for example, not more than 5 mass%, for example, not more than 3 mass%, for example, not more than 2% by weight, for example, not more than 1 mass%.

Unless otherwise stated, under the impurities understand other compounds, that is not the stereoisomers or enantiomers. In one implementation, under the impurities understand other connections, and other stereoisomers. In one implementation, under the impurities understand other compounds and other enantiomer.

In one embodiment, the implementation is essentially purified form is optically pure measures at the 60% (i.e. 60% of the compound, the calculation in moles, is a desired stereoisomer or enantiomer and 40% represents the unwanted stereoisomer or enantiomer), for example, optically pure, at least 70%, for example, optically pure, at least 80%, for example, optically pure, at least 90%, for example, optically pure, at least 95%, for example, optically pure, at least 97%, for example, optically pure, at least 98%, for example, optically pure, at least 99%.

Isomers

Some compounds according to the present invention may exist in one or more different geometric, optical, enantiomeric, diasteriomeric, epimeric, tropicheskih, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to enumerated, CIS - and TRANS-forms; E - and Z-forms; C-, t - and r-forms; endo - and Exo-forms; R-, S-, and meso-forms; D - and L-forms; d - and I-forms; (+) and (-) forms; keto-, enol -, and enolate forms; SYN - and anti-forms; syncline and anticline forms; α - and β-forms; axial and Equatorial forms; forms "boats", "chairs", "twisting", "envelope" and "magazines" and their combinations, then United under the name "isomers" (or "isomeric forms").

The authors of the present invention note that, with the exception discussed below tautomeric forms, in the present about what Isani intentionally from the term "isomers" excluded structural (or systemic) isomers, (i.e. isomers that differ in the connections between the atoms other than differences in the spatial positions). For example, the reference of the methoxy group, -och3should not be construed as a reference to its structural isomer, hydroxymethylene group, -CH2HE. Similarly, the reference to orthocarbonic should not be construed as a reference to its structural isomer metalorganic. However, the reference to the class of structures may include structurally isomeric forms that fall under this class (for example, C1-7alkyl includes n-propyl and ISO-propyl; butyl includes n-, ISO-, sec - and tert-butyl; methoxyphenyl includes ortho-, meta-, and parametersetter).

The above exception does not apply to tautomeric forms, for example, keto-, enol and enolate forms, as, for example, the following tautomeric pairs: ketone/enol (illustrated below), Imin/enamine, amide/iminspect, amicin/amidin, nitroso/oxime, thioketone/ential, N-nitroso/hydroxilase, and nitro/acentro.

The authors note that the term "isomer" is specifically included compound with one or more isotopic substitutions. For example, H may be in any isotopic form, including1H,2N (D) and3N (T); C may be in any isotopic group, including12C,13C and14With; may be in any isotopic form, including16O and18O; itomo similar.

Unless expressly stated, a reference to a particular connection covers all such isomeric forms, including mixtures thereof (e.g. racemic mixtures). Methods of cooking (e.g., asymmetric synthesis) and separation (e.g. fractional crystallization and chromatography) such isomeric forms or known to experts in the field, or they can easily be obtained through the adaptation referred to in this description of how, through well-known techniques.

Salt

It may be convenient or desirable to prepare, purify and/or work with the appropriate salt of the compounds according to the present invention, for example, pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts" J.Pharm. Sci., Vol.66, pp.1-19.

For example, if the compound is anionic in nature or has a functional group which may be anionic in nature (for example, -COOH may be-soo-), then you can get its salt with a suitable cation. Examples of suitable inorganic cations include, but are not limited to enumerated, ions of alkali metals such as Na+and K+, alkaline earth metals such as CA2+and Mg2+and other cations, such as Al+3. Examples of suitable organic cations include, but are not limited Chivas listed, ion ammonium (i.e.) and substituted ammonium ions (e.g., NH3R+,,). Examples of some suitable substituted ammonium ions are derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, Ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylendiamine, choline, meglumine and tromethamine, as well as amino acids such as lysine and arginine. An example of a conventional Quaternary ammonium ion is.

If the connection is cationic in nature or contains a functional group that can turn into a cationic group (e.g.,- NH2can bethen it is possible to obtain the salt of the compound with a suitable anion. Examples of suitable inorganic anions include, but are not limited to enumerated, anions derived the following inorganic acids: hydrochloric, Hydrobromic, itestosterone, sulfuric, sulfurous, nitric, nitrous, phosphoric and phosphorous.

Examples of suitable organic anions include, but are not limited to enumerated, anions derived the following organic acids: 2-acetoxybenzoic, acetic, ascorbic, aspartic acid, camphorsulfonate, cinnamon, lemon, ethylendiaminetetraacetic, ethicolegal, econsultancy, fumaric, glucoheptonate, gluconic, glutamic, glycolic, hydroxymaleimide, hydroxymatairesinol, isetionate, lactic, lactobionic, lauric, maleic, malonic, methansulfonate, mucus, oleic, oxalic, palmitic, Paveway, Pantothenic, phenylacetic, vinylsulfonate, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluensulfonate and valerianic. Examples of suitable polymeric organic anions include, but are not limited to the above, the anions derived the following polymeric acid, tannic acid, carboxymethyl cellulose.

Unless expressly stated, a reference to a particular compound also includes its salt form.

The solvate and hydrate

It may be convenient or desirable to prepare, purify and/or work with the appropriate MES connection. The term "MES" in the present description is used in its traditional sense, it refers to the complex solute (for example, the compounds, salts of compounds) and the solvent. If water is the solvent, the MES may traditionally be called a hydrate, such as a monohydrate, dihydrate, trihydrate and so on.

Chemically protected form

It may be convenient or desirable to prepare, purify and/or operate in connection with a chemically protected form. The term "chemically protected form" in the present description is used in the conventional chemical sense, and refers to the connection in which one or more of the reactive functional groups protected from unwanted chemical reactions at specific settings (e.g., pH, temperature, radiation, solvent and the like). In practice, for reversible impart a functional group, which is otherwise under particular conditions would be reactive, reactionary resistance applied by well-known chemical methods. In a chemically protected form one or more reactive functional groups is in protected form, or a protective group (also known as masked or masking group or blocked or blocking group). Protecting reactive functional group can carry out reactions involving unprotected reactive functional groups, without affecting the protected group, the protective group can be removed, usually at a later stage, not significantly affecting about who headed the remainder of the molecule. See, for example, Protective Groups in Organic Synthesis (.Green and P.Wuts; 3rd Edition; John Wiley and Sons, 1999).

Unless expressly stated, a reference to a particular compound also includes its chemically protected form.

In chemical synthesis are well known and widely used a great variety of ways such "protection," "blocking" or "masking". For example, a compound having two non-identical reactive functional groups, both of which under certain conditions would become reactive, can be derivatization thus, to make a "protected", and because directionspanel under these certain conditions, one of these functional groups; protected thus the connection can be used as a reagent, which actually has only one reactive functional group. After the desired reaction (containing another functional group), "protection" can be removed, while previously protected functional group acquires its inherent functionality.

For example, the hydroxyl group can be protected, either (OR, a simple ester) or (-OC(=O)R, ester), for example, in the form of: tert-butyl ether; a benzyl, benzhydryl (diphenylmethylene) or tretilova (triphenylmethyl) ether; trimethylsilyloxy or tert-buildiers the purple ether; or acetylator ester (-OC(=O)CH3-SLA).

For example, aldehyde or ketone group can be protected as acetal (R-CH(OR)2or Catala (R2C(OR)2), respectively, in which the carbonyl group (>C=O) becomes W (>C(OR)2), by reaction with, for example, a primary alcohol. Aldehyde or ketone group can easily be regenerated by hydrolysis in a large excess of water in the presence of acid.

For example, the amino group can be protected by conversion into the amide (-NRCO-R) or a urethane (-NRCO-OR), for example, in the form: methylamide (-NHCO-CH3); benzylcyanide

(-NHCO-OCH2C6H5, -NH-Cbz); such as tert-butoxide (-NHCO-OC(CH3)3, -NH-Boc); a 2-diphenyl-2-propoxylated (-NHCO-OC(CH3)2With6H4With6H5, -NH-Bpoc), 9-fluorenylacetamide (-NH-Fmoc), as a 6-nitroferricyanide (-NH-Nvoc), 2-trimethylsilylacetamide (-NH-Teoc), as a 2,2,2-trichloroacetamide

(-NH-Troc), as allelochemical (-NH-Alloc), as

2(-phenylsulfonyl)ethylacetamide (-NH-Psec); or, in suitable cases (e.g., cyclic amines), as nitroxide radical (>N-O•).

For example, an acidic carboxyl group can be protected in the form of ester, for example, With1-7Olkiluoto ester (e.g. methyl ester; tert-butyl ether);1-7halogenosilanes ether (EmOC is emer, C1-7trialgenericuh ether); three1-7alkylsilane-C1-7Olkiluoto ether or5-20aryl-C1-7Olkiluoto ether (for example, benzyl ether; nitrobenzyl ether) or in the form of an amide, for example methylamide.

For example, Tilney group can be protected as thioether (-SR), for example, in the form: benzoylthiourea; acetamidomethyl ether (-S-CH2NHC(=O)CH3).

Prodrugs

It may be convenient or desirable to prepare, purify and/or work with a connection in the form of prodrugs. The term "prodrug"used in the present description, refers to the connection from which you metabolism (e.g., in vivo), produces the desired active compound. Typically, the prodrug is inactive or less active than the desired active compound, but may provide advantages in handling, inserting or metabolic properties.

Unless expressly stated, a reference to a particular compound also includes its prodrug.

For example, some prodrugs are esters of active compounds (for example, physiologically acceptable and metabolically labile ether complex). In the metabolism of ester group (-C(=O)OR), is cleaved to form the active drug. Such esters may be formed by esterification, for example,any carboxyl group (-C(=O)OH) in the parent compound, when, if necessary, prior protection of any other reactive group present in the parent compound, followed by removal of the protection, if required.

Some prodrugs are activated enzyme with the formation of the active compound or compounds, which after further chemical reaction to form the active compound (e.g., ADEPT, GDEPT, LIDEPT, and so on). For example, the prodrug may be a carbohydrate derivative or other conjugate with glycoside or may be a derived complex ester of the amino acids.

Chemical synthesis

In the present description describes some of the methods of chemical synthesis of compounds derived BCSA according to the present invention. Within the scope of the claims of the present invention, in order to facilitate the synthesis of additional compounds listed here, and/or other well known methods can be modified and/or adapted.

Application

Connection - derived BCSA disclosed in the present description, can be useful, for example, in the treatment of diseases and conditions that are alleviated when the inhibition of TACE.

Use in methods of inhibiting TACE and ways to regulate the release of cytokines

One aspect of the present invention described relates to what we in this application the method of inhibiting TACE in a cell in vitro or in vivo, comprising bringing into contact the specified cells and an effective amount of the compound-derived BCSA.

Proper analysis to determine the inhibition of TACE known to specialists in this field and/or described in this application.

Another aspect of the present invention is described in the present application is the method of regulating (e.g., ingibirovaniya) release of cytokines (e.g., release of TNF-α in the cell in vitro or in vivo, comprising the bringing into contact of the specified cells and an effective amount of the compound - derived BCSA.

Proper analysis to determine the regulation (e.g., inhibiting) the release of cytokines known to specialists in this field and/or described in this application.

In one implementation, the specified method is performed in vitro.

In one implementation, the specified method is performed in vivo.

In one embodiment, the implementation of connection - derived BCSA provide in the form of a pharmaceutically acceptable composition.

Treatment can be applied to any cell type, including but not limited to enumerated, the cells of the lungs, gastrointestinal (including, for example, cells of the intestine, colon), breast cancer (breast, ovarian, prostate, liver (hepatitis the e), kidney (renal), bladder, pancreas, brain and skin.

Use in methods of therapy

Another aspect of the present invention relates to the use of compounds derived BCSA described in this application, for the treatment (for example, diseases or disorders in a human or animal through therapeutic effect.

Used in the production of medicines

Another aspect of the present invention relates to the use of compounds derived BCSA described in this application in the manufacture of a medicine for treatment (for example, diseases or disorders).

In one embodiment, the implementation of the drug contains a compound - derived BCSA.

Methods of treatment

Another aspect of the present invention relates to a method of treatment (for example, diseases or disorders), comprising the administration to a patient in need of treatment a therapeutically effective amount of the compound - derived BCSA described in this application, preferably in the form of pharmaceutical compositions.

Treatable condition - condition mediated TAS

In one embodiment, the implementation (for example, when using treatments for the production of pharmaceuticals or medical treatment) this treatment is predstavljaet a treatment of a disease or disorder, mediated by TACE, for example, a disease or disorder, about which it is known that it is mediated by TACE.

The disease or disorder mediated by TACE, represents, for example, a disease or disorder in which TAS and/or activity of TACE are important or necessary, for example, for the emergence, development, manifestation, and so forth of the disease or disorder.

Treatable condition - States, facilitated by the inhibition of TACE

In one embodiment, the implementation (for example, when using treatments for the production of pharmaceuticals, methods of treatment, said treatment is the treatment of a disease or disorder, which is facilitated by inhibition of TACE, for example, diseases or disorders, about which it is known that it facilitates the inhibition of TACE.

Treatable condition States that cure inhibitors TAS

In one embodiment, the implementation (for example, when using treatments for the production of pharmaceuticals, methods of treatment), the treatment is a treatment of a disease or disorder, about which it is known that it can be treated by TACE inhibitor.

Treatable condition - specific state

In one embodiment, the implementation (for example, when applying the methods of therapy, when production is the tion of drugs, methods of treatment, said treatment is the treatment of rheumatoid arthritis; inflammation; psoriasis; septic shock; graft rejection; cachexia; anorexia; congestive heart failure; postischemic injury associated with reperfusion injury; inflammatory diseases of the Central nervous system, inflammatory bowel disease; insulin resistance; HIV infection; cancer; chronic obstructive pulmonary disease (COPD) or asthma.

In one embodiment, the implementation (for example, when using treatments for the production of pharmaceuticals, methods of treatment, said treatment is the treatment of osteoarthritis, ulcerative colitis, Crohn's disease, multiple sclerosis or degenerative loss of cartilage.

In one implementation of the present invention, said treatment is the treatment of inflammation.

In one implementation of the present invention, the treatment is a treatment of rheumatoid arthritis.

In one implementation, the treatment is a treatment of psoriasis.

Treatable condition - cancer, etc.

In one implementation of the present invention, the treatment is a treatment of cancer.

In one implementation, the specified treatment is a treatment for: lung cancer, melcochita the CSOs lung cancer, non-small cell lung cancer, cancer of the gastrointestinal tract, stomach cancer, bowel cancer, colon cancer, rectal cancer, cancer of the colon and rectum, thyroid cancer, breast cancer, ovarian cancer, endometrial cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, reallocations carcinoma, ovarian cancer, pancreatic cancer, brain cancer, glioma, sarcoma, osteosarcoma, bone cancer, skin cancer, squamous cell carcinoma, Kaposi's sarcoma, melanoma, malignant melanoma, lymphoma, or leukemia.

In one implementation, the specified treatment is a treatment:

cancer, for example carcinoma of the bladder, breast, colon (e.g. carcinomas of the colon and rectum, such as adenocarcinoma of colon cancer and adenoma of the colon, carcinoma of the kidney, squamous cell carcinomas, carcinoma of liver, lung, for example adenocarcinoma, small cell lung cancer and non-small cell lung cancer), esophagus, gall bladder, ovary, pancreas e.g. exocrine pancreatic carcinoma), stomach, cervix, thyroid, prostate, skin (e.g., squamous cell carcinoma);

hematopoietic tumors of lymphoid system, for example leukemia, acute lymphocytic leukemia, B-cleto is Noah lymphoma, T-cell lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma, Volosovo-cell lymphoma or lymphoma Barchetta;

hematopoietic tumors melodey system, for example acute and chronic myelogenous leukemia, myelodysplasia syndrome, or promyelocytic leukemia;

tumors of mesenchymal origin, such as fibrosarcoma or rhabdomyosarcoma;

tumor of the Central or peripheral nervous system, for example astrocytoma, neuroblastoma, glioma or sanomi;

melanoma; seminomy; teratocarcinoma; osteosarcoma; xenoderoma pigmentosum; keratoacanthoma; follicular thyroid cancer or Kaposi's sarcoma.

In one implementation, the specified treatment is a treatment of solid cancer.

In one embodiment, the implementation (for example, when using treatments for the production of pharmaceuticals, methods of treatment, said treatment is the treatment of hyperproliferative skin disorder.

In one implementation, the treatment is a treatment of psoriasis, senile keratosis and/or skin cancer non-melanoma.

Treatable condition is inflammation, etc.

In one embodiment, the implementation (for example, when using treatments for the production of pharmaceuticals, methods of treatment, said treatment is the first treatment of inflammatory diseases.

In one implementation, the treatment is a treatment of inflammatory diseases, including pathological activation of T - and b-cell lymphocytes, neutrophils and/or basophils.

In one implementation, the specified treatment is a treatment of inflammatory diseases such as rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella, psoriatic arthritis and other arthritic conditions; Alzheimer's disease; toxic shock syndrome, inflammatory reaction induced by endotoxin or inflammatory bowel disease; tuberculosis, atherosclerosis, muscle degeneration; Reiter syndrome; gout; acute synovitis; sepsis; septic shock; endotoxic shock; gram-negative sepsis, respiratory pathological syndrome adults, cerebral malaria, chronic pneumonia, silicosis, sarcoidosis lungs; diseases associated with resorption of bone tissue; injury associated with ischemic reperfusion, reactions, graft rejection; rejection of allogeneic transplant; fever and myalgias due to infection, such as influenza, cachexia, in particular, cachexia secondary to infection or malignancy, cachexia secondary to acquired syndrome immunodefi the ITA (AIDS); AIDS; ARC (complex related to AIDS; education keloid zone; the formation of scar tissue; Crohn's disease; ulcerative colitis; hyperthermia; chronic obstructive pulmonary disease (COPD); acute respiratory distress syndrome (ARDS); asthma; pulmonary fibrosis; bacterial pneumonia.

In one of the preferred options for implementing said treatment is the treatment of arthritic conditions, including rheumatoid arthritis and rheumatoid spondylitis; inflammatory bowel disease, including Crohn's disease and ulcerative colitis, and chronic obstructive pulmonary disease (COPD).

In one preferred implementation options, said treatment is the treatment of inflammatory disorders characterized by the proliferation of T-cell activation and growth of T cells), for example, rejection of a tissue implant, endotoxic shock, and glomerular nephritis.

Treatment

The term "treatment" used in the present description in the context of treatment of a condition generally refers to treatment and therapy, both human and animal (e.g., in veterinary applications), in which achieve some desired therapeutic effect, such as inhibition of the progression of the condition, and includes a reduction in the speed of progression, stopping the progression, lightweight and strong the of the symptoms of the condition, improvement and therapeutic status. Also included treatment as a preventative measure (i.e. prevention). For example, use in patients whose condition has not yet developed, but have the risk of state, also covered by the term "treatment".

For example, treatment of cancer includes cancer prevention, reducing the incidence of cancer, relief of the symptoms of cancer, etc.

The expression "therapeutically effective amount"used in the present description, refers to that amount of the compound or material, or composition, or dosage forms containing the compound, which after the introduction in accordance with the desired mode of treatment is effective to create some desired therapeutic effect, commensurate with a reasonable ratio of benefit/risk.

Concomitant therapy

The term "treatment" includes the combined treatment and combination therapy, in which, for example, sequentially or simultaneously, combine two or more courses of treatment or therapy. For example, compounds derived BCSA described in this application can also be used in courses of combination therapy, for example, in combination with other agents, such as other inhibitors of TACE, other cytotoxic agents, other anti-cancer agents, and so forth. Examples of courses Le is to be placed and therapies include, not limited to enumerated, chemotherapy (administration of active agents, including, for example, drugs, antibodies (e.g., immunotherapy), prodrugs (e.g., in photodynamic therapy, GDEPT, ADEPT, and so on); surgery; radiation therapy; photodynamic therapy and controlled diet.

For example, it may be useful to combine the treatment with compound - derived BCSA described in this application with one or more (e.g. 1, 2, 3, 4) agent or therapy, regulating cell growth or survival of cells, or differentiation of cells of different mechanism, thus affecting several characteristic features of cancer.

One aspect of the present invention is described in the present application is connection - derived BCSA in combination with one or more additional therapeutic agent, as described below.

The particular combination will relate to the competence of the doctor who will choose the dosage, applying General knowledge, and dosage regimes known practice in this area.

Agents (i.e. compounds derived BCSA described in this application, plus one or more other agents) can be administered simultaneously or sequentially, and you can enter in individually varying dose regimens and different ways. For example, when consequently the m introduction allowed the introduction of agents in closely spaced points in time (for example, through a period of 5-10 minutes) or longer intervals (e.g. 1, 2, 3, 4 or more hours apart, or even, if necessary, over longer periods of time, adjusting the exact mode of administration with the properties of therapeutic agent(s).

Agents (that is, derived BCSA connections described in this application, plus one or more other agents) may jointly enter into the formulation of the same dosage form or another, individual agents can be introduced in the formulation separately and you can ensure together in the form of a set, possibly with instructions on their application.

Other applications

Described in this application connection - derived BCSA can also be used as additives to the cell cultures for the inhibition of TACE, for inhibiting the release of cytokines (e.g., release of TNF-α), and so on.

Described in this application connection - derived BCSA also can be used as part of in vitro studies, for example, to determine the probability that the test object will benefit from the treatment under consideration by the connection.

Described in this application connection - derived BCSA can also be used as a standard for research for other compounds, other inhibitors of TACE and the AK next.

Sets

One aspect of the present invention refers to the set containing (a) described in the present application is a connection - derived BCSA, or a composition containing the described in the present application is the connection, for example, preferably in a suitable container and/or with suitable packaging; and (b) instructions for use, for example, written instructions on how to enter the specified compound or composition.

Written instructions may also include a list of indications for which the active ingredient will provide adequate treatment.

Route of administration

Connection - derived BCSA or pharmaceutical composition comprising the compound - derived BCSA, you can enter the subject of any convenient routes of administration, or systemic/peripheral image, or topically (for example, in place of the desired action).

Methods of introduction include, but are not limited to enumerated: oral method (e.g., swallowing); transbukkalno; transdermal (including for example, pad, patch, and so on); transmucosally (including for example, pad, patch, and so on); intranasal (e.g., nasal spray); ocular (e.g., eye drops); pulmonary (e.g., inhalation or insufflation therapy using an aerosol, e.g. through mouth or nose); rectal (e.g., a suppository is or klistira); vaginal (for example, the pessary); parenteral, for example, by injection, including subcutaneous, transcutaneous, intramuscular, nutionul, intraarterial, intracardial, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal injection; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.

The subject/patient

The subject/patient may be Hardouin, vertebrate, a mammal, a placental mammal, a marsupial (e.g., kangaroo, wombat), a rodent (e.g. a Guinea pig, hamster, rat, mouse), murine (e.g. a mouse), Reztsova (e.g., a rabbit), avian (e.g., bird), canids (e.g., a dog), feline (e.g. a cat), equine (e.g. a horse), pig-like (e.g., a pig), sheep (e.g., a sheep), bovine (e.g., cow), the primacy or primoabruzzi (e.g. a monkey or APE), a monkey (e.g., marmoset, baboon), an APE (e.g., gorilla, chimpanzee, orangutan, Gibbon), or a person.

Moreover, the subject/patient may be in any form of development, for example in the form of fruit.

In one preferred implementation entity/pacie the fact is the man.

Composition

Although you can enter the connection - derived BCSA itself, it is preferable to provide it as a pharmaceutical formulation (e.g., composition, preparation, medication)containing at least one described in the present application compound, together with one or more pharmaceutically acceptable ingredients well known to specialists in this field, including, but not limited to, pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, antioxidants, lubricants, stabilizers, soljubilizatorami, surfactants (e.g., wetting agents), masking agents, colorants, flavorings and sweeteners. The composition may further contain other active agents, for example, other therapeutic and prophylactic agents.

Thus, the present invention further provides the above pharmaceutical compositions and methods of preparation of pharmaceutical compositions by mixing at least one compound - derived BCSA described in this application, together with one or more pharmaceutically acceptable ingredients well known to specialists in this area, such as a carrier, diluent, the former is pienta etc. When introduced into the formulation in the form of discrete units (e.g. tablets, and so forth) each unit contains a predetermined quantity (dose) of the connection.

The expression "pharmaceutically acceptable", as used in this application, refers to compounds, ingredients, materials, compositions, dosage forms, etc. that according to competent medical judgment, suitable for the implementation of their contact with the tissues of the examined subject (e.g. human) without the danger of excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable ratio of benefit/risk. Each carrier, diluent, excipient etc. must also be "acceptable" in the sense of compatibility with the other ingredients specified composition.

Suitable carriers, diluents, excipients, and so forth can be found in standard pharmaceutical texts, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pa., 1990; and Handbook of Pharmaceutical Excipients. 2nd edition, 1994.

The composition can be prepared by any means well known to experts in the field of pharmaceutics. Such methods include the implementation phase of the Association of the compounds according to the present invention with a carrier consisting of one or more auxiliary ingredient. In General, the composition goth is let through uniform and direct Association connections with the media (for example, liquid carriers, finely dispersed solid media, and so on), and then, if necessary, shaping the product form.

The composition can be prepared in such a way as to ensure rapid or slow release; immediate, delayed, timed or maintenance release or a combination of different specified types of release.

Composition depending on requirements can be obtained in the form of liquid solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil in water, water in oil), elixirs, syrups, medicinal cereals, rinses, drops, tablets (including, for example, coated tablets, granules, powders, pellets, pastilles, capsules (including, for example, hard and soft gelatine capsules, starch capsules, granules, capsules, boluses, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, mists or aerosols.

Composition depending on requirements can be obtained in the form of plaster, adhesive plaster, tires, tires or the like, impregnated one or more connection and possibly one or more pharmaceutically acceptable ingredient, including, for example, penetration enhancers, infiltration and absorption. Composition depending on requirements can be obtained in the form of the e depot or reservoir.

The connection according to the present invention can be dissolved, suspended or mixed with one or more pharmaceutically acceptable ingredient. The connection can be provided in the form of liposomes and other microparticles intended for targeted delivery of compounds, for example, blood components or one or more of the body.

The composition may be suitable for oral administration (e.g., swallowing) include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil in water, water in oil), elixirs, syrups, medicinal clover, tablets, granules, powders, capsules, starch wafers, pills, capsules, boluses.

Compositions suitable for buccal introduction, include rinsing, pellets, tablets, and pads, adhesive patches, depots and tanks. Pellet typically include a connection-based flavouring flavouring substances, usually sucrose and acacia gums or tragakant. Tablets typically contain the compound in an inert matrix, such as gelatin and glycerine sucrose and gum acacia. Rinse typically contain the compound in a suitable liquid carrier.

Compositions suitable for sublingual administration, include tablets, pellets, lozenges, capsules and pills.

Compositions suitable for administration through the mucosa of Obolo is at the mouth, include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil in water, water in oil), rinse, pellets, tablets, and pads, adhesive patches, depots and tanks.

Compositions suitable for administration through mucous membranes, non-oral mucosa include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil in water, water in oil), suppositories, pessaries, gels, pastes, ointments, creams, lotions, oils and pads, adhesive patches, depots and tanks.

Compositions suitable for percutaneous introduction, include gels, pastes, ointments, creams, lotions and oils, as well as pads, adhesive plasters, bandages, dressings, depots and tanks.

Tablets can be manufactured in a traditional way, for example by compression or molding, possibly with one or more auxiliary ingredient. Compressed tablets can be prepared by compressing in a suitable machine, the compound in free-flowing form such as powder or granules, possibly mixed with one or more binding agents (e.g., povidone, gelatin, gum acacia, sorbitol, tragakant, hypromellose); fillers or diluents (e.g., lactose, microcrystalline who cellulose, the calcium phosphate); lubricants (e.g. magnesium stearate, talc, silica gel); disintegrants (for example, sodium salt starch glycolate, cross-linked povidone, cross-linked sodium salt of carboxymethyl cellulose); surface-active or dispersing or wetting agents (e.g. sodium salt of lauryl sulphate), preservatives (e.g. methyl ether by parahydroxybenzoic acid, propyl ester by parahydroxybenzoic acid, sorbic acid), flavorings, flavor enhancers and flavor and sweeteners. Molded tablets can be made in a suitable machine by casting a mixture of the powdered compound moistened with an inert liquid diluent. Tablets can be coated or make corrugated so as to provide slow or controlled release, applying in different proportions, for example, hypromellose, in order to provide the desired release profile. Additionally, the tablets may provide coverage, for example, to affect the release of, for example, coating, dissolving in the intestines, to provide release in parts of the gastrointestinal tract other than the stomach.

Ointments are typically prepared from compounds in paraffin or mixing the I water ointment basis.

Creams typically are made of compounds and oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example, at least about 30% wt./mass., a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof. The local composition may preferably include a compound that increases absolu, or the penetration of compounds through the skin or other affected area. Examples of such compounds that enhance penetration through the skin, include dimethyl sulfoxide and related analogues.

Emulsions are typically prepared from compounds and oil phase may contain only emulsifying agent (otherwise known as an emulgent), or this phase can contain a mixture of at least one emulsifier with a fat or oil, or grease, and oil. Preferably hydrophilic emulsifier include together with a lipophilic emulsifier, which acts as a stabilizer. It is also preferable to include both oil and fat. Together, the emulsifier(s), in the presence or in the absence of stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and/or fat is the so-called emulsifying materials, forming oil is ing the dispersion phase of the cream compositions.

Suitable emulsifiers and emulsion stabilizers include Tween 60, Span 80, cetosteatil alcohol, ministerului alcohol, glycerol monostearate and sodium salt of lauryl sulphate. The choice of suitable oils or fats for the composition based on achieving the desired cosmetic properties, since the solubility of the compound in most oils that are commonly used in the pharmaceutical compositions of the emulsion, can be very low. So, the cream should be a preferably low-fat, no coloring and wash off the product with the consistency to avoid leakage from tubes or other containers. You can apply unbranched or branched mono - or dienone alkalemia esters, such as digitariat, isolatedstore, discouny ester of propylene glycol, dienone esters of fatty acids coconut isopropylmyristate, decillia, isopropyl, butilstearat, 2-ethylhexylamine or you can apply a mixture of branched esters known as Crodamol cap, and three of the latter esters are preferred. They can be used by themselves or in combination, depending on the required properties. Alternatively, you can apply lipids with high melting points, such as white soft paraffin or other mineral oils.

It is notizie intranasal liquid media include, for example, a nasal spray, nasal drops, or compositions for aerosol injection containing spray with water or oil solutions of the connection.

Compositions for intranasal solid media include, for example, a large powder with particle diameters in the range from approximately 20 to 500 microns which is administered as it is customary to introduce the medicinal powder for insertion through the nose, that is, a rapid inhalation through the nasal passage from a container of powder, which is kept located close to the nose.

Compositions for pulmonary administration (e.g., inhalation or insufflation therapy) include compounds obtained in the form of an aerosol spray in the package under pressure with the use of a suitable propellant (propellant), such as DICHLORODIFLUOROMETHANE, Trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.

Compositions suitable for ocular injection, include eye drops, in which the compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the connection.

Compositions suitable for rectal administration, can be presented as a suppository with a suitable base comprising, for example, natural or hydrogenated oils, waxes, fats, semi-liquid or liquid polyols, for example the aslo cocoa or salicylate; or a solution or suspension for treatment klistira.

Compositions suitable for vaginal administration, can be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the connection of such media that are experts in this field consider acceptable.

Compositions suitable for parenteral administration (e.g. by injection), include aqueous or non-aqueous, isotonic, pyrogen-free, sterile fluid (e.g., solutions, suspensions), in which the compound is dissolved, suspended or concluded otherwise (for example, in a liposome or other microparticle). Such fluid may additionally contain other pharmaceutically acceptable ingredients, such as antioxidants, buffer mixture, preservatives, stabilizers, bacteriostatic, suspendresume agents, thickeners and dissolved substances, indicating the composition isotonicity with blood (or another related to this application fluid of the body) the intended recipient. Examples of excipients include, for example, water, alcohols, polyols, glycerine, vegetable oils and the like. Examples of suitable isotonic media for use in such compositions include sodium chloride solution for injection, ringer's or lactate ringer's solution. Typically the concentration is in fluid the STI range from about 1 ng/ml to about 10 μg/ml, for example from about 10 ng/ml to about 1 μg/ml of the Composition can be delivered in standard containers for single dosing or multidose sealed containers, such as vials or bottles, and can be stored in a freeze-dried state (liofilizirovannom state), requiring only the addition of sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets.

Dosage

Specialist in the art will take into account that appropriate dosages of the compounds derived BCSA, and compositions containing compounds derived BCSA, can vary from patient to patient. Determining the appropriate dosage will depend on the balance of the level of therapeutic benefit against any risk or deleterious side effects. The selected dosage level will depend on many factors, including, but not limited to the above: the activity of the particular compound, the route of administration, time of administration, method of excretion of the compound, the duration of the treatment, other drugs, compounds and/or materials used in combination, the severity of the condition, as well as species, sex, age, weight, condition is, General health and prior medical history of the patient. The number of joints and the method of administration, in the end, will be at the discretion of the physician, veterinarian, or Clinician, although generally the choice of dose is chosen in such a way as to reach the site of action of concentrations, causing the desired effect without showing significant toxic or harmful side effects.

During the course of treatment introduction can be performed in a single dose, continuously or periodically (for example, divided doses at intervals of time). How to determine the most effective methods of administration and dosages are well known to specialists in this area and will vary depending on the composition used for therapy, the purpose of therapy, the type of cell targeted therapy, and treatable entity. The choice of the attending physician, veterinarian or Clinician can apply levels of dosage and mode of administration.

In General, a suitable daily dose of a compound - derived BCSA is in the range from about 100 μg to about 250 mg (more typically from about 100 μg to about 25 mg) per kilogram body weight of the subject. Regardless of whether the connection salt, complex ether, amidon, prodrug, or the like, enter the amount calculated on the basis of the parent compounds, p is oportional increasing the estimated mass of the body.

EXAMPLES

The following examples described in this application, are given only to illustrate the present invention and are not intended to limit the scope of his claims.

Total synthesis

Cyclic sulfonamidnuyu derivatives (5.1)-(5.68) were prepared as follows (Scheme 1). Sulfonylamine amines (2.1)-(2.61) sulphonylchloride (1.1)-(1.8) was carried out by heating, providing cyclization. Some esters (3) were isolated and hydrolyzed under acidic conditions to form the corresponding carboxylic acid (4). Some intermediate esters (3) transformed into carboxylic acid (4) without selection by prolonged heating in the same reaction vessel, which resulted in hydrolysis of the ester functions. Carboxylic acid (4.1)-(4.68) was converted into the corresponding hydroxamic acid (5.1)-(5.68)using one of three methods (Conditions a-C, Scheme 1).

Scheme 1

Sulphonylchloride (1.1), (where R1=R2=R3=H)used in the synthesis of sulfonamides (5.1)-(5.61), prepared by well-known methods (see, e.g., Finn et al., 2005). Sulphonylchloride (1.2)-(1.6)required for the synthesis of sulfonamides (5.62)-(5.66), prepared regioselective chlorosulfonylisocyanate known unsaturated esters (7.1)-(7.5) (see, for example, Imashiro, 2004; Westman et al., 2001; El-P.le et al., 2007; Mahajan et al., 2005; Sretas et al., 2007).

Scheme 2

Sulphonylchloride (1.7)-(1.8), required for the synthesis of sulfonamides (5.67)-(5.68), prepared on the basis of aminobenzenesulfonic acid (8.1)-(8.2) (Scheme 3). They were assigned to diazonium salts (9.1)-(9.2), which are then used in the Heck reaction, receiving unsaturated esters (10.1)-(10.2). Intermediate compound (10.1)-(10.2) by reaction with chloride tiomila translated in sulphonylchloride (1.7)-(1.8).

Scheme 3

Amines (2.1)-(2.42)used in the synthesis of compounds (5.1)-(5.42), it was in stock. Amines (2.43)-(2.44)required in the synthesis of sulfonamides (5.43)-(5.44), received by the O-alkylation parahydroxylated (11) but-2-in-1-yl-methanesulfonate (12) (see, for example, Brummond et al., 2004) and 4-chloromethyl-2-methylinosine (13) (see, for example, Duan et al., 2002) with the formation of anilines (2.43) and (2.44), respectively (Scheme 4).

Scheme 4

Amines (2.45)-(2.61)required in the synthesis of sulfonamides (5.45)-(5.61), received the O-alkylation of parahydroxybenzoic (14) alkylating agents (15.1)-(15.17) and subsequent reduction of the nitro group in the resulting intermediate compounds (16.1)-(16.17), using to restore one of the three reaction conditions (Scheme 5, the conditions a-C).

Scheme 5

Alkiliruyusciye agents (15.1)-(15.7)required for the synthesis of anilines (2.45)-(2.51), it was in stock. Alkylating agents (15.8)-(15.11)required for the synthesis of anilines (2.52)-(2.55), prepared by the literature methods (see, for example, White et al., 1982; Jackson et al., 1988; Thibault et al., 2006; Marshall et. al., 2000).

Alkylating agent (15.12)required in the synthesis of aniline (2.56), prepared by the method shown in Scheme 6. 2-Methyl-4-hydroxymethylcytosine (17) was oxidized by periodinane Dess-Martin with the formation of the aldehyde. Adding bromide Metalmania to the intermediate aldehyde led to a secondary alcohol, which was treated with methanesulfonamide with the formation of alkylating agent (15.12).

Scheme 6

4-Chlormethine (15.13)required in the synthesis of aniline (2.57), prepared from the known 4-hydroxymethylcytosine (18) (see, for example, Boutros et.al., 2000) (Scheme 7).

Scheme 7

Synthesis alkiline the General agents (15.14) and (15.15), required for the preparation of anilines (2.58) and (2.59), started from carboxylic acids (19.1) and (19.2), which was prepared by the methods described in the literature (see, e.g., Yen et al., 1958; Buchman et al., 1946) (Scheme 8). Carboxylic acid (19.1) and (19.2) translated in their esters, which are then restored to alcohols. These intermediate products were transferred into the desired chloromethylpyridine (15.14) and (15.15) by reaction with chloride tiomila.

Scheme 8

Synthesis of 4-chloromethylpyridine (15.16) and (15.17)required for the preparation of anilines (2.60) and (2.61), conducted on the basis of derivatives of 4-methylpyridine (20.1) and (20.2) (Scheme 9). Alcohols (21.1) and (21.2) prepared by well-known scheme (see, for example, Ragan et al., 2002) and translated in 4-chloromethylpyridine (15.16) and (15.17).

Scheme 9

For the preparation of hydroxamic acids (24) sulphonylchloride (1.1) first translated in unsaturated ester (23) by reaction with a substituted aniline (22) (Scheme 10). Reaction of ester (23) with hydroxylamine in the basic conditions led to intramolecular cyclization and formation of hydroxamic acids (24).

Scheme 10

Synthesis of hydroxamic acids (29) is shown in Scheme 11. The free hydroxyl group of the intermediate compound (16.7) (Scheme 5) meticuliously. Methanesulfonate group was replaced by sidegroups, the Ded was restored and received Amina protected amino group, tert-butoxycarbonyl group, receiving the intermediate compound (25). The restoration of the nitro group resulted in aniline (26), the reaction of which with sulphonylchloride (1.1) has led to the cyclic carboxylic acid (27). Carboxylic acid is transformed into hydroxamic acid (28), N-tert-butoxycarbonyl protective group, which was tsalala with the formation of the final product (29) in the form of a hydrochloric salt.

Scheme 11

Hydroxamic acid (36) prepared according to Scheme 12. Known unsaturated ester (30) (see, for example, Eberbach et al., 1986) regioselective was chlorantraniliprole and the product (31) was used for the reaction with aniline (2.1) with the formation of cyclic ether complex (32). Phenolic hydroxyl group was sulfonylureas anhydride triftormetilfullerenov acid and the resulting product (33) was used in the reaction of a combination of Suzuki of Miyaura with phenylboronic acid. Ester group in the intermediate compound (34) is hydrolyzed, and carboxylic acid (35) was transferred into the hydroxamic acid (36).

Scheme 12

Hydroxamic acid (39) prepared from cyclic ether complex (32). His On-alkilirovanie and the product (37) hydrolyzed with the formation of carboxylic acid (38), which, in turn, translated into hydroxamic acid (39).

Scheme 13

Synthesis of hydroxamic acids (43) is described by figure 14. The reaction sulphonylchloride (1.8) with aniline (2.1) has led to an unsaturated ether complex (40). It has been used in combination with phenylboronic acid under Suzuki-Miyaura with the formation of intermediate compounds (41), which was subjected to cyclization and subsequent hydrolysis with the formation of carboxylic acid (42), in turn, transformed into hydroxamic acid (43).

Scheme 14

Hydroxamic acid (48.1) and (48.2) was prepared from commercially available sulfonamides (44.1) and (44.2) (Scheme 15). They were treated with lithium in ortopedici and functionally converted into the sulfonamide (see, for example, MacNeil et al., 2001) with subsequent ladirovannye, which resulted in intermediate products (45.1) and (45.2). The reaction Hake of arisitide (45.1) and (45.2) with methyl acrylate resulted in cyclic esters (46.1) and (46.2). Their hydrolyzed to carboxylic acid (47.1) and (47.2), and additionally transformed into hydroxamic acid (48.1) and (48.2).

Scheme 15

Hydroxamic acid (54.1)-(54.9) prepared using a different approach (Scheme 16). Sulfonamides (50.1)-(50.9) was obtained from commercially available sulphonylchloride (49.1)-(49.9) and used for the reaction of direct orthonitrophenyl - formirovaniya with the formation of intermediate compounds (51.1)-(51.9). The reaction is Oia referirovanija these intermediate compounds have led to cyclic ethers (52.1)-(52.9), which were hydrolysed to the acids (53.1)-(53.9), then transformirovannykh in hydroxamic acid (54.1)-(54.9).

Scheme 16

The sulfonamide (50.10) prepared from sulphonylchloride (49.10) and used for the reaction of orthonitrophenyl - formirovaniya. This has led to dehalogenation product (51.10), which later transformed into hydroxamic acid (54.10), using the already-described synthetic route (Scheme 17).

Scheme 17

Hydroxamic acid (54.11) received by the Circuit 18. The sulfonamide (50.11) prepared from sulphonylchloride. (At 49.11) was subjected to reaction orthonitrophenyl-formirovaniya education promezhutochnogo connection (51.11). The latter was used in the reaction of referirovanija with the formation of the product 52.11, in which the group of fluorine substituted matography. The latter was further transformed into hydroxamic acid (54.11) by known procedures.

Scheme 18

Cyclic intermediate product (51.5) led to the product (52.12)containing the group of fluorine, the reaction of referirovanija substituted in addition to the product (52.5) methoxy group (Scheme 19). Cyclic ester (52.12) transformed into hydroxamic acid (54.12), applying accepted procedures.

Scheme 19

Hydro is sambuu acid (57) was prepared from compound ether (3.1) (Scheme 20). It was restored and the resulting primary alcohol is transformed into the chloride. Chloride was replaced by cyanide with the formation of intermediate (55), which was hydrolyzed and the resulting carboxylic acid (56) additionally transformed into hydroxamic acid (57).

Scheme 20

Synthesis of hydroxamic acids (62.1)-(62.2) was performed according to Scheme 21. Sulfonamides (59.1)-(59.2)prepared from sulphonylchloride (58.1)-(58.2), transformed into esters of carboxylic acids (60.1)-(60.2), according to previously published sequences (see, for example, Takahashi et al., 2003). Esters (60.1)-(60.2) hydrolyzed, and the resulting carboxylic acid (61.1)-(61.2) was converted into hydroxamic acid (62.1)-(62.2).

Scheme 21

Stereoisomers of cyclic sulfonamides (5.1), (5.43) and (5.44) were prepared in enantiomerically pure form (Scheme 22). For this purpose, (R)-phenylglycinol has azetilirovanie racemic acids (4.1), (4.43) and (4.44) with the formation of the corresponding amides in the form of a mixture of diastereomers (S,R)-(63.1), (63.2), (63.3) and (RR)-(63.1), (62.3), (63.3), which were separated chromatographically. Divided amides (S,R)-(63.1), (63.2), (63.3) and (R,R)-(63.1), (63.2), (63.3) were hydrolysed to enantiomerically pure isomers of the acid (S)-(4.1), (4.43), (4.44) and (S)-(4.1), (4.43), (4.44)which were then converted into enantiomerically pure hydroxamic acid (+)-(5.1), (+)-(5.43), (+)-(5.44 and (-)-(5.1), (-)-(5.43) and (-)-(5.44).

Scheme 22

Hydroxamic acids (72) was prepared as follows (Scheme 23). Salicylic aldehyde (64) was treated with N,N-dimethylthiocarbamate education THIOCARBAMATE (65). It was introduced in the rearrangement Newman-Quart, getting S-carbamoylmaleamic aldehyde (66). Karbamoilnuyu group in (66) tsalala MeONa, and the resulting tiolet in situ alkilirovanie methyl-benzyl, getting S-benzyldimethylamine aldehyde (67). Subsequent Wittig reaction with aldehyde (67) led to unsaturated ether complex (68). Sulfide group in a complex ester (68) was oxidized with the formation of sulfone (69), which is transformed in the supported NaHCO3intramolecular Michael's reaction in cyclic product (70). Hydrolysis of ester (70) in acidic conditions led to a carboxylic acid (71), which translated into hydroxamic acid (72).

Scheme 23

Hydroxamic acid (77) prepared on the basis of known sulfonamida (73) (see, for example, Goulaouic-Dubois et al., 1995). The sequence of reactions orthonitrophenyl and iodization has led to the iodide (74), which was used in the Heck reaction with methyl acrylate with the formation of the cyclic ether complex (75). It hydrolyzed to carboxylic acid (76), later transformed into hydrox the MoEHE acid (77).

Scheme 24

General procedure for preparation of the methyl esters of(E)-3-(2-chlorosulfonylphenyl)acrylic acid (1.2)-(1.6)

Method a: Chlorosulfonic acid (3.5 ml, 52 mmol) was cooled in an ice bath and added to it the unsaturated ester (7) (1.0 g, 5.2 mmol). The cooled mixture was stirred until the disappearance of starting material (control by TLC, from 30 minutes to 6 hours) and carefully poured into ice-cold water. In the case of sediment, it was collected on a filter, washed with water and dried under vacuum with the formation of products (1). If the sediment is not excluded, the aqueous phase was extracted with CHCl3combined organic phase was dried over Na2SO4and the solvent was removed under vacuum with the formation of the crude product (1), which was used in the next stage without additional purification.

Following the method similar to method A, in the form of a crude product were obtained the following compounds.

SynthesisMethodNameStructure
1AndMethyl ester (E)-3-(2-chlorosulfonyl-5-methoxyphenyl)acrylic acid (1.2)
2AndMethyl ester (E)-3-(7-chlorosulfonyl-2,3-dihydrobenzo[1,4]dioxin-6-yl)acrylic acid (1.3)
3AndMethyl ester (E)-3-(2-chlorosulfonyl-4,5-acid)acrylic acid (1.4)
4AndMethyl ester (E)-3-(2-chlorosulfonyl-3,4,5-trimethoxyphenyl)acrylic acid (1.5)
5AndMethyl ester (E)-3-(2-chlorosulfonyl-3,5-acid)acrylic acid (1.6)

Connection (1.2): Grey powder (0.88 g, 59%).1H-NMR (CDCl3, TMS (tetramethylsilane was)) δ: 3.85 (3H, s); 3.94 (3H, s); 6.41 (1H, d, 15 Hz); 7.01 (1H, dd, 2 Hz and 9 Hz); 7.16 (1H, d, 2 Hz); 8.07 (1H, d, 9 Hz) and 8.46 ppm (ppm) (1H, d, 15 Hz).

General procedure for the synthesis of the methyl esters of (E)-3-(2-chlorosulfonylphenyl)acrylic acid (1.7) and (1.8)

Method: 2-Aminobenzenesulfonic acid (8) (10 mmol) suspended in sulfuric acid (5 ml) and the reaction with the ect was cooled in an ice bath. To the mixture was added 40% aqueous solution of NaNO2(2 ml)and the mixture was stirred for 1 hour. Added Et2O and the precipitate collected on the filter. Received the crude product (9) (2.35 g), suspended in DMF (dimethylformamide) (7 ml) under inert atmosphere was added Pd2(dba)3(30 mg), and then the methyl ester of acrylic acid (2.7 mmol, 30 mmol). The reaction mixture was stirred at room temperature for 10 hours, the Solvent was evaporated under vacuum to give crude sulfonic acid (10). Thereto was added toluene (7 ml) and chloride thionyl (5.5 ml, 80 mmol). The resulting mixture was boiled under reflux for 4 h, cooled to room temperature and filtered. The solution was concentrated under vacuum with the formation of the crude product (1.7) or (1.8).

Following a technique similar to the method in the form of a crude product were obtained the following compounds.

td align="center"> In
SynthesisMethodNameStructure
6InMethyl ester (E)-3-(2-chlorosulfonyl-4-were)acrylic acid (1.7)
7Methyl ester (E)-3-(2-chlorosulfonyl-4-bromophenyl)acrylic acid (1.8)

Synthesis of 8

4-(But-2-in-1 yloxy)phenylamine (2.43)

A mixture of sulphate parahydroxylated (11) (395 mg, 2.5 mmol), but-2-in-1-ylmethanone (12) (370 mg, 2.5 mmol) and Cs2CO3(2,44 g, 7.5 mmol) in DMF (10 ml) was heated at 60°C for 6 hours the Mixture was poured into water (50 ml) and was extracted with EtOAc (20 ml). The organic phase was separated and dried over Na2SO4. The solution was filtered and evaporated with the formation of the crude product (2.43) (140 mg, 35%) as a dark oil used in the next stage without additional purification.1H-NMR (CDCl3, TMS) δ: 1.84 (3H, t, 2 Hz); 4.53 (2H, m); 6.62 (2H, d, 8 Hz) and 6.78 ppm (2H, d, 8 Hz).

Synthesis of 9

4-(2-Methylinosine-4-metiloksi)aniline (2.44)

A mixture of sulphate parahydroxylated (11) (207 mg, 1 mmol), hydrochloric salt of 4-chloromethyl-2-methyl-quinoline (13) (228 mg, 1 mmol) and Cs2CO3(1.63 g, 5 mmol) in DMF (5 ml) was stirred at room temperature for 3 hours the Mixture was poured into water (50 ml) and was extracted with EtOAc (20 ml). The organic phase was separated and dried over Na2SO4. The solution was filtered and evaporated. The residue was purified flash chromatography on silica gel,elwira EtOAc, with the formation of the product (2.44) (165 mg, 63%).1H-NMR (CDCl3, TMS) δ: 2.73 (3H, s); 3.9 (2H, br s); 5.40 (2H, s); 6.65 (2H, d, 9 Hz); 6.85 (2H, d, 9 Hz); 7.44 (1H, s); 7.50 (1H, t, 8 Hz); 7.68 (1H, t, 8 Hz); 7.90 (1H, d), and 8.07 ppm (1H, d, 8 Hz).

General method of preparation of anilines (2.45)-(2.61)

Method: 4-NITROPHENOL (14) (3.1 g, 2.2 mmol), alkylating agent (15) and K2CO3(920 mg, 6.7 mmol) suspended in DMF (7 ml). The resulting suspension was stirred at room temperature for 48 h and was poured into water (70 ml). The product was treated with EtOAc (70 ml). The organic phase was separated and washed with saturated brine (70 ml). The extract was dried over Na2SO4was filtered and the solvent was removed under vacuum with the formation of almost pure intermediate product (16).

For the synthesis of anilines (2.45) and (2.46), intermediate products (16.1) and (16.2) (6.5 mmol) was dissolved in EtOH (15 ml), and to the solution was added 10% Pd/C (95 mg). The mixture was stirred in an atmosphere of H2until complete conversion of starting material (about 4 hours). The mixture was passed through a column telicom, and the solvent was removed under vacuum with the formation crude anilines (2.45) and (2.46). In the synthesis of aniline (2.48)as the hydrogenation catalyst used Raney Nickel.

In the synthesis of anilines (2.47) (2.49)-(2.61) the corresponding intermediate products (16) (0.3 mmol) was dissolved in methanol (2 ml), to the solution was added Na2S×9H2O (1) - Rev. Mol), and the mixture was heated to education phlegmy until complete conversion of starting material (about 2 hours). The solvent was removed under vacuum and the residue was distributed between water and EtOAc. The organic phase was dried over Na2SO4, was filtered and was evaporated. The residue was purified using column chromatography on silica gel and was used in the next stage without purification.

Following a technique similar way, the following compounds were obtained as crude products.

SynthesisMethodNameStructure
104-(2-Diethylaminoethoxy)aniline (2.45)
114-(2-Morpholine-4-yl-ethoxy)aniline (2.46)
124-Allyloxyphenyl (2.47)
134-(Pyridine-4-ylethoxy)aniline (2.48)
144-(Pyridine-3-ylethoxy)aniline (2.49)
154-(Pyridine-2-ylethoxy)aniline (2.50)

SynthesisMethodNameStructure
164-(4-Aminophenoxy)but-2-in-1-ol (2.51)
174-Penta-2-injectionin (2.52)
184-Prop-2-injectionin (2.53)
194-Prop-2-injectionin (2.54)
20 4-(1-Methyl-but-2-ynyloxy)aniline (2.55)
214-[1-(2-Methyl-quinoline-4-yl)ethoxy]aniline (2.56)
224-(Quinoline-4-ylethoxy)aniline (2.57)
234-(6-fluoro-2-methyl-quinoline-4-ylethoxy)aniline (2.58)
244-(6-Chloro-2-methyl-quinoline-4-ylethoxy)aniline (2.59)

SynthesisMethodNameStructure
254-(2-Methylpyridin-4-ylethoxy)aniline (2.60)
26

General procedure for preparation of methyl esters (1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (3.1)-(3.3), (3.26)-(3.29), (3.44)-(3.46), (3.48)-(3.50), (3.56)-(3.66)

Method D: To a solution of chloride of sulfonyl (1) (1 mmol) and amine (2) (1 mmol) in dioxane (5 ml) was added 1M aqueous solution of NaHCO3(3 ml). The resulting mixture was stirred at room temperature for 2 hours and then boiled under reflux for 2 hours. After cooling to room temperature was added water (20 ml) and EtOAc (20 ml). The organic phase was separated and washed with saturated saline (20 ml) and dried over Na2SO4. The solution was filtered and evaporated, and the residue was purified flash chromatography on silica gel, elwira a mixture of light petroleum ether and EtOAc.

Following the method similar to method D, in the form of a crude product were obtained the following compounds.

SynthesisMethodNameStructure
27DMethyl ester 2-(1,1-dioxo-2-phenyl-2,3-dihydro-6-benzo[d]isothiazol-3-yl)uksu the Noah acid (3.1)

SynthesisMethodNameStructure
28DMethyl ester 2-(2-naphthalene-2-yl-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (3.2)
29DMethyl ester 2-(1,1-dioxo-2-metatool-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (3.3)
30DMethyl ester 2-[1,1-dioxo-2-(4-pyrrol-1-yl-phenyl)-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]-acetic acid (3.26)
31DMethyl ester 2-[2-(4-imidazol-1-yl-phenyl)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]acetic acid (3.27)
32DMetrowater 2-[1,1-dioxo-2-(4-[1,2,4]triazole-1-yl-phenyl)-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]acetic acid (3.28)

SynthesisMethodNameStructure
33DMethyl ester 2-[2-(4-oxazol-5-yl-phenyl)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]acetic acid (3.29)
34DMethyl ether {2-[4-(2-methylinosine-4-ylethoxy)-phenyl]-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl}acetic acid (3.44)
35DMethyl ester 2-{2-[4-(2-Dimethylaminoethoxy)phenyl]-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl}acetic acid (3.45)
36DMethyl ester 2-{2-[4-(2-morpholine-4-ylethoxy)-phenyl]-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl}acetic acid (3.46)
37 DMethyl ester 2-{1,1-dioxo-2-[4-(pyridine-4-ylethoxy)phenyl]-2,3-dihydro-1H-benzo[d]isothiazol-3-yl}-acetic acid (3.48)

SynthesisMethodNameStructure
38DMethyl ester 2-{1,1-dioxo-2-[4-(pyridine-3-ylethoxy)phenyl]-2,3-dihydro-1H-benzo[d]isothiazol-3-yl}-acetic acid (3.49)
39DMethyl ester 2-{1,1-dioxo-2-[4-(pyridine-2-ylethoxy)phenyl]-2,3-dihydro-1H-
benzo[d]isothiazol-3-yl}-acetic acid (3.50)
40DMethyl ester 2-(2-{4-[1-(2-Methylinosine-4-yl)ethoxy]-phenyl}-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)-acetic acid (3.56)
41DMethyl ester 2-{1,1-dioxo-2-[4-(quinoline-4-ylethoxy)phenyl]-2,3-di is Idro-1H-benzo[d]isothiazol-3-yl}-acetic acid (3.57)
42DMethyl ester 2-{2-[4-(6-fluoro-2-methyl-quinoline-4-ylethoxy)-phenyl]-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl}-acetic acid (3.58)

SynthesisMethodNameStructure
43DMethyl ester 2-{2-[4-(6-chloro-2-methyl-quinoline-4-ylethoxy)-phenyl]-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl}-acetic acid (3.59)
44DMethyl ester 2-{2-[4-(2-methylpyridin-4-ylethoxy)phenyl]-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl}acetic acid (3.60)
45DMethyl ester 2-[4-(2,6-dimethylpyridin-4-ylethoxy)-phenyl]-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl}acetic acid (3.61)
46DMethyl ester of 2-(5-methoxy-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (3.62)
47DMethyl ester 2-(1,1-dioxo-2-phenyl-2,3,6,7-tetrahydro-1H-5,8-dioxine-2-azacyclopenta [b]naphthalene-3-yl)acetic acid (3.63)

SynthesisMethodNameStructure
48DMethyl ester of 2-(5,6-dimethoxy-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (3.64)
49DMethyl ester of 2-(5,6,7-trimetoksi-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (3.65)
50DMethyl ester of 2-(5,7-dimethoxy-1,1-dioxo-2-FeNi the -2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (3.66)

Connection (3.1): Yield 61%,1H-NMR (CDCl3, TMS) δ: 2.74 (1H, dd, 8 Hz and 16 Hz); 2.97 (1H, dd, 4 Hz, band 16 Hz); 3.59 (3H, s); 5.58 (1H, dd, 4 Hz and 8 Hz); 7.3-7.7 (8H, m) and 7.89 ppm (1H, d, 8 Hz).

Compound (3.2): Yield 71%,1H-NMR (DMSO-d6, TMS) δ: 3.01 (2H, d, 5 Hz); 3.29 (3H, s); 5.92 (1H, t, 5 Hz) and 7.5-8.0 ppm (11N, m).

Connection (3.3): Exit 23%,1H-NMR (CDCl3, TMS) δ: 2.40 (3H, s); 2.77 (1H, dd, 8 Hz and 16 Hz); 2.97 (1H, dd, 4 Hz and 16 Hz); 3.61 (3H, s); 5.56 (1H, dd, 4 Hz and 8 Hz); 7.1-7.7 (7H, m), and 7.89 ppm (1H, d, 8 Hz).

The compound (3.62): Yield 66%,1H-NMR (CDCl3, TMS) δ: 2.76 (1H, dd, 8 Hz and 16 Hz); 2.96 (1H, dd, 4 Hz and 16 Hz); 3.60 (3H, s); 3.70 (3H, s); 3.89 (3H, s); 5.53 (1H, dd, 4 Hz and 8 Hz); 6.9-7.5 (7H, m), 7.77 ppm (1H, d, 8 Hz).

General methods of preparation of 2-(1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (4)

Method E: of esters (3). A solution of ester (3) (1 mmol) in a mixture of dioxane (20 ml) and concentrated aqueous HCl (5 ml) was stirred at room temperature for 2 days. The solvent was evaporated and replaced with fresh dioxane (20 ml) and concentrated aqueous HCl (5 ml). Stirring is continued an additional two days, until complete disappearance of starting material (control TCXI; if necessary, the solvent system was changed again). The solvent was evaporated with the formation of the product (4).

Method F: sulphonylchloride (1) and amines (2). To the R. is the target of chloride sulfonyl (1) (1 mmol) and amine (2) (1 mmol) in dioxane (5 ml) was added 1 M aqueous solution of NaHCO 3(3 ml). The resulting mixture was stirred at room temperature for 2 hours and then boiled under reflux for 8 hours. After cooling to room temperature was added water (20 ml) and EtOAc (20 ml). The aqueous phase was separated and acidified to pH about 2 with concentrated aqueous HCl and was extracted with EtOAc (20 ml). The organic phase was washed with saturated saline (20 ml) and dried over Na2SO4. The solution was filtered and evaporated to education in the rest of the product (4) (content of approximately 30-80%). In most cases it was used in further reactions without purification.

Following methods similar to method E or method F, were obtained crude products of the following compounds.

SynthesisMethodNameStructure
51E2-(1,1-dioxo-2-phenyl-2,3-dihydro-6-benzo[d]isothiazol-3-yl)acetic acid (4.1)

SynthesisMethodNameArt is ucture
52E2-(2-Naphthalene-2-yl-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (4.2)
53E2-(1,1-Dioxo-2-metatool-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (4.3)
54F2-(1,1-Dioxo-2-paratool-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (4.4)
55F2-(1,1-Dioxo-2-orthotopic-2,3-dihydro-1H-benzo[C-]isothiazol-3-yl)acetic acid (4.5)
56F2-[2-(2-Methoxyphenyl)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]acetic acid (4.6)
57F2-[2-(3-Methoxyphenyl)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]acetic acid (4.7)

SynthesisMethodNameStructure
58F2-[2-(4-Methoxyphenyl)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]acetic acid (4.8)
59F2-[2-(3-Phenoxyphenyl)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]acetic acid (4.9)
60F2-[2-(4-Chlorophenyl)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]acetic acid (4.10)
61F2-[2-(3-Methylsulfinylphenyl)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]acetic acid (4.11)
62F2-[2-(3-Triptoreline)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]acetic acid (4.12)
63F2-[2-(3-Triptoreline)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]acetic acid (4.13)

SynthesisMethodNameStructure
64F2-[2-(4-Itfinal)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]acetic acid (4.14)
65F2-(2-Diphenyl-3-yl-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (4.15)
66F2-[2-(4-Forfinal)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]acetic acid (4.16)
67F2-[2-(4-Triptoreline)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]acetic acid (4.17)
68F2-[2-(4-
Triptoreline)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]acetic acid (4.18)

SynthesisMethodNameStructure
69F2-[1,1-Dioxo-2-(4-triftormetilfullerenov)-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]-acetic acid (4.19)
70F2-[1,1-Dioxo-2-(4-Methylsulfinylphenyl)-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]acetic acid (4.20)
71F2-[1,1-Dioxo-2-(4-ethylphenyl)-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]-acetic acid (4.21)
72F2-[1,1-Dioxo-2-(4-isopropylphenyl)-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]acetic acid (4.22)
73F2-(2-Diphenyl-4-yl-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (4.23)

SynthesisMethodNameStructure
74F2-[1,1-Dioxo-2-(4-phenoxyphenyl)-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]acetic acid (4.24)
75F2-[2-(4-Benzyloxyphenyl)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]acetic acid (4.25)
76E2-[1,1-Dioxo-2-(4-pyrrol-1-yl-phenyl)-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]acetic acid (4.26)
77E2-[2-(4-Imidazol-1-yl-phenyl)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]acetic acid (4.27)
78E2-[1,1-Dioxo-2-(4-[1,2,4]triazole-1-yl-phenyl)-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]acetic acid (4.28)

SynthesisMethodNameStructure
79E2-[2-(4-Oxazol-5-yl-phenyl)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]acetic acid (4.29)
80F2-{2-[4-(2-Methylthiazole-4-yl)phenyl]-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl}-acetic acid (4.30)
81F2-[2-(4-Dimethylaminophenyl)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]acetic acid (4.31)
82F2-[2-(4-(Morpholine-4-yl-phenyl)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]kasna acid (4.32)
83F2-[2-(4-Ethoxyphenyl)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]acetic acid (4.33)

SynthesisMethodNameStructure
84F2-[2-(4-Butoxyphenyl)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]acetic acid (4.34)
85F2-{1,1-Dioxo-2-[4-(2,2,2-Triptoreline)phenyl]-2,3-dihydro-1H-benzo[d]isothiazol-3-yl}acetic acid (4.35)
86F2-[2-(3-Forfinal)-1,1-dioxo-2,3-dihydro-1H-
benzo[d]isothiazol-3-yl]acetic acid (4.36)
87F(1,1-Dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (437)
88F2-(2-Methyl-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (4.38)
89F2-(2-Benzyl-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (4.39)
90F2-[2-(6-Methoxypyridine-3-yl)-1,1-dioxo-2,3-dihydro-benzo[d]isothiazol-3-yl]acetic acid (4.40)

SynthesisMethodNameStructure
91F2-(2-Cyclohexyl-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (4.41)
92F2-(1-Benzylpiperidine-4-yl)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]acetic acid (4.42)
93F2-[2-(4-But-2-injectively)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]acetic acid (4.43)
94E2-{2-[4-(2-Methylinosine-4-ylethoxy)phenyl]-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl}acetic acid (4.44)
95EHydrochloric salt of {2-[4-(2-dimethylaminoethoxy)-phenyl]-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl}-acetic acid (4.45)

SynthesisMethodNameStructure
96EHydrochloric salt of 2-{2-[4-(2-dimethylaminoethoxy)-phenyl]-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl}-acetic acid (4.46)
972-[2-(4-Allyloxyphenyl)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]acetic acid (4.47)
98E2-{1,1-Dioxo-2-[4-(pyridine-4-ylethoxy)phenyl]-2,3-dihydro-1H-benzo[d]isothiazol-3-yl}-acetic acid (4.48)
99E2-{1,1-Dioxo-2-[4-(pyridine-3-ylethoxy)phenyl]-2,3-dihydro-1H-benzo[d]isothiazol-3-yl}-acetic acid (4.49)
100E2-{1,1-Dioxo-2-[4-(pyridine-2-ylethoxy)phenyl]-2,3-dihydro-1H-benzo[d]isothiazol-3-yl}-acetic acid (4.50)

SynthesisMethodNameStructure
101F2-{2-[4-(4-Hydroxy-but-2-ynyloxy)-phenyl]-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl}acetic acid (4.51)
102F2-[1,1-Dioxo-2-(4-Penta-2-ynyloxy-phenyl)-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]acetic acid (4.52)
103F2-[1,1-Dioxo-2-(4-prop-2-ynyloxy-phenyl)-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]acetic acid (4.53)
104F2-[2-(4-but-3-enyloxy-phenyl)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]acetic acid (4.54)
105F2-[2-(4-but-3-enyloxy-phenyl)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]acetic acid (4.55)

SynthesisMethodNameStructure
106E2-(2-{4-[1-(2-Methylinosine-4-yl)ethoxy]-phenyl}-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic who Isleta (4.56)
107E2-{1,1-Dioxo-2-[4-(quinoline-4-ylethoxy)phenyl]-2,3-dihydro-1H-benzo[d]isothiazol-3-yl}-acetic acid (4.57)
108E2-{2-[4-(6-fluoro-2-methylinosine-4-ylethoxy)-phenyl]-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl}acetic acid (4.58)
109E2-{2-[4-(6-Chloro-2-methylinosine-4-ylethoxy)-phenyl]-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl}-acetic acid (4.59)
110E2-[4-(2-Methylpyridin-4-ylethoxy)-phenyl]-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl}acetic acid (4.60)

SynthesisMethodNameStructure
111E 2-[4-(2,6-Dimethylpyridin-4-ylethoxy)phenyl]-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl}acetic acid (4.61)
112E2-(5-Methoxy-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (4.62)
113E2-(1,1-Dioxo-2-phenyl-2,3,6,7-tetrahydro-1H-5,8-dioxine-2-azacyclopenta [b]naphthalene-3-yl)acetic acid (4.63)
114E2-(5,6-Dimethoxy-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (4.64)
115E2-(5,6,7-Trimetoksi-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (4.65)

SynthesisMethodNameStructure
116E2-(5,7-Dimethoxy-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (4.66)
117F2-(6-Methyl-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (4.67)
118F(6-Bromo-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (4.68)

Connection (4.1): Yield 65%, the melting point of 178-179°C (with decomposition),1H-NMR (DMSO-d6, TMS) δ: 2.73 (1H, dd, 7 Hz and 16 Hz); 2.91 (1H, dd, 4 Hz and 16 Hz); 5.70 (1H, t, 5 Hz); 7.3-7.6 (5H, m), 7.6-8.1 ppm (4H, m).

Connection (4.2): Yield 64%,1H-NMR (DMSO-d6, TMS) δ: 2.83 (1H, dd, 5 Hz and 16 Hz); 2.94 (1H, dd, 5 Hz and 16 Hz); 5.86 (1H, t, 5 Hz) and 7.5-8.1 ppm (11N, m).

Connection (4.3): Exit 23%,1H-NMR (DMSO-d6, TMS) δ: 2.35 (3H, s); 2.72 (1H, dd, 4 Hz and 16 Hz); 2.90 (1H, dd, 7 Hz and 16 Hz); 5.67 (1H, t, 5 Hz); 7.16 (1H, d, 7 Hz); 7.2-7.4 (3H, m); 7.6-7.9 (3H, m) and 7.95 ppm (1H, d, 7 Hz).

Connection (4.43): Yield 61%, melting point 160-161°C,1H-NMR (DMSO-d6, TMS) δ: 1.86 (3H, t, 2 Hz); 2.73 (1H, dd, 16 Hz and 6 Hz); 2.85 (1H, dd, 16 Hz and 4 Hz); 4.79 (2H, d, 2 Hz); 5.50 (1H, t, 5 Hz); 7.06 (2H, d, 9 Hz); 7.42 (2H, d, 9 Hz); 7.6-7. (3H, m); 7.94 (1H, d, 8 Hz) and 12.42 ppm (less than 1H, br s).

Connection (4.44): Yield 32%,1H-NMR (DMSO-d6, TMS) δ: 2.67 (3H, s); 2.79 (2H, m); 5.51 (1H, br t, ~5 Hz); 5.63 (2H, s); 7.26 (2H, d, 9 Hz); 7.45 (2H, d, 9 Hz); 7.5-7.8 (6N, m); 7.95 (2H, t, 7 Hz) and 8.11 ppm (1H, d, 8 Hz).

The compound (4.62): Yield 37%,1H-NMR (DMSO-d6, TMS) δ: 2.78 (1H, dd, 6 Hz and 16 Hz); 2.91 (1H, dd, 4 Hz and 16 Hz); 3.88 (3H, s); 5.63 (1H, t, 5 Hz); 7.2-7.6 (7H, m) and 7.95 ppm (1H, d, 7 Hz).

General methods of preparation of (1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)-N-hydroxyacetamido (5)

Method G: To a solution of carboxylic acid (4) (1 mmol) in CH2Cl2(10 ml) was added chloride anhydride, oxalic acid (0,43 ml, 5 mmol) and a drop of DMF. The resulting mixture was stirred at room temperature and was evaporated. To the residue was added a mixture obtained by dissolving hydrochloric salt of hydroxylamine (347 mg, 5 mmol) in a mixture of THF, (THF, tetrahydrofuran (THF), (5 ml) and 1M aqueous NaHCO3(5 ml). The resulting suspension was stirred for 15 minutes and was distributed between EtOAc (50 ml) and water (30 ml). The organic phase was separated and washed with saturated NaHCO3(20 ml) and saturated saline (20 ml). The solution was dried over Na2SO4, was filtered and was evaporated. The product was purified using preparative obremeniaet chromatography and/or crystallization.

Method N: CDI (4.5 mmol, 1.5 equivalent) was added to a solution of carboxylic acid (4) (3.0 mmol) Vahom THF (5 ml). The reaction mixture was stirred for 1 hour To the mixture was added thinly pounded hydrochloric salt of hydroxylamine (417 mg, 6 mmol). The obtained heterogeneous mixture was stirred overnight (about 16 hours). The mixture was diluted with 5% aq. KHSO4(30 ml) and was extracted with EtOAC (2×30 ml). The combined organic phase was washed with saturated saline solution (30 ml) and dried over Na2SO4. The extract was filtered and concentrated under vacuum with the formation of the crude product. The product (5) was purified using preparative obremeniaet chromatography and/or crystallization.

Method I: a Mixture of carboxylic acid (4) (0.24 mmol), O-tritylodontidae (66 mg, 0.24 equivalent), EDCl, 1-ethyl-3-(3-dimethylpropyleneurea)carbodiimide, (33 mg, 0.24 mg) and HOBt, hydroxybenzotriazole (46 mg, 0.24 mmol) in DMF (2.4 ml) was stirred overnight and then was diluted with saturated aqueous NaHCO3(25 ml). The resulting mixture was extracted with EtOAc (3×20 ml) and the combined organic phase was washed with saturated saline (20 ml). The extract was dried over Na2SO4, was filtered and was evaporated. The residue was purified by flash chromatography on silica gel, elwira light petroleum ether and EtOAc. Received hydroxamic acid, protected O-trition (0,17 mmol)and 10% (volume/volume) triftormetilfullerenov acid was dissolved in DCM (dihormati is (e). The mixture was stirred at room temperature for 1 h and added Meon (1 ml). The solvents were removed under vacuum, and the residue was purified using preparative obremeniaet chromatography with formation of the product (5).

Following methods similar to Method G, Method N or the Way I received the following compounds in the form of a crude product.

SynthesisMethodNameStructure
119G2-(1,1-Dioxo-2-phenyl-2,3-dihydro-6-benzo[d]isothiazol-3-yl)-N-hydroxyacetamido (5.1)
120G2-(2-Naphthalene-2-YL-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)-N-hydroxyacetamido (5.2)
121G2-(1,1-Dioxo-2-metatool-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)-N-hydroxyacetamido (5.3)

Synthesis MethodNameStructure
122G2-(1,1-Dioxo-2-paratool-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)-N-hydroxyacetamido (5.4)
123G2-(1,1-Dioxo-2-orthotopic-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)-N-hydroxyacetamido (5.5)
124G2-[2-(2-Methoxyphenyl)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]-N-hydroxyacetamido (5.6)
125G2-[2-(3-Methoxyphenyl)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]-N-hydroxyacetamido (5.7)
126G2-[2-(4-Methoxyphenyl)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]-N-hydroxyacetamido (5.8)

Synthesis MethodNameStructure
127G2-[2-(3-Phenoxyphenyl)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]-N-hydroxyacetamido (5.9)
128G2-[2-(4-Chlorophenyl)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]-N-hydroxyacetamido (5.10)
129G2-[2-(3-Methylsulfinylphenyl)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]-N-hydroxyacetamido (5.11)
130G2-[2-(3-Triptoreline)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]-N-hydroxyacetamido (5.12)
131G2-[2-(3-Triptoreline)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]-N-hydroxyacetamido (5.13)

SynthesisMethodNameStructure
132G2-[2-(4-Itfinal)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]-N-hydroxyacetamido (5.14)
133G2-(2-Diphenyl-3-yl-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)-N-hydroxyacetamido (5.15)
134G2-[2-(4-Forfinal)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]-N-hydroxyacetamido (5.16)
135G2-[2-(4-Triptoreline)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]-N-hydroxyacetamido (5.17)
136G2-[2-(4-Triptoreline)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]-N-hydroxyacetamido (5.18)

SynthesisMethodNameStructure
137N2-[1,1-Dioxo-2-(4-triftormetilfullerenov)-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]-N-hydroxyacetamido (5.19)
138N2-[1,1-Dioxo-2-(4-methylsulfinylphenyl)-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]-N-hydroxyacetamido (5.20)
139N2-[1,1-Dioxo-2-(4-ethylphenyl)-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]-N-hydroxyacetamido (5.21)
140G2-[1,1-Dioxo-2-(4-isopropylphenyl)-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]-N-hydroxyacetamido (5.22)
141N2-(2-Diphenyl-4-yl-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)-N-hydroxyacetamido (5.23)

SynthesisMethodNameStructure
142G2-[1,1-Dioxo-2-(4-phenoxyphenyl)-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]-N-hydroxyacetamido (5.24)
143G2-[2-(4-Benzyloxyphenyl)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]-N-hydroxyacetamido (5.25)
144N2-[1,1-Dioxo-2-(4-pyrrol-1-ylphenyl)-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]-N-hydroxyacetamido (5.26)
145N2-[2-(4-Imidazol-1-yl-phenyl)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]-N-hydroxyacetamido (5.27)
146N2-[1,1-Dioxo-2-(4-[1,2,4]triazole-1-yl-phenyl)-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]-N-
hydroxyacetamido (5.28)

SynthesisMethodNameStructure
147N2-[2-(4-Oxazol-5-yl-phenyl)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]-N-hydroxyacetamido (5.29)
148N2-{2-[4-(2-Methylthiazole-4-yl)phenyl]-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl}-N-hydroxyacetamido (5.30)
149G2-[2-(4-Dimethylaminophenyl)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]-N-hydroxyacetamido (5.31)
150G2-[2-(4-(Morpholine-4-ylphenyl)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]-N-hydroxyacetamido (5.32)
151G2-[2-(4-Ethoxyphenyl)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-and the]-N-hydroxyacetamido (5.33)

SynthesisMethodNameStructure
152G2-[2-(4-Butoxyphenyl)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]-N-hydroxyacetamido (5.34)
153G2-{1,1-Dioxo-2-[4-(2,2,2-triptoreline)phenyl]-2,3-dihydro-1H-benzo[d]isothiazol-3-yl}-N-hydroxyacetamido (5.35)
154G2-[2-(3-Fluoro-phenyl)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]-N-hydroxyacetamido (5.36)
155G2-(1,1-Dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)-N-hydroxyacetamido (5.37)
156G2-(2-Methyl-1,1-dioxo-2,3-dihydro-1H-
benzo[d]isothiazol-3-yl)-N-hydroxyacid the MFA (5.38)
157G2-(2-Benzyl-1,1-dioxo-2,3-dihydro-1H-
benzo[d]isothiazol-3-yl)-N-hydroxyacetamido (5.39)
158G2-[2-(6-Methoxy-pyridin-3-yl)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]-N-hydroxyacetamido (5.40)

SynthesisMethodNameStructure
159N2-(2-Cyclohexyl-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)-N-hydroxyacetamido (5.41)
160N2-[2-(1-Benzylpiperidine-4-yl)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]-N-hydroxyacetamido (5.42)
161G2-[2-(4-But-2-injectively)-1,1-dioxo-2,3-dihydro-1H-benzo[d]is societal-3-yl]-N-hydroxyacetamido (5.43)
162G2-{2-[4-(2-Methylinosine-4-ylethoxy)phenyl]-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl}-N-hydroxyacetamido (5.44)
163G2-{2-[4-(2-Dimethylaminoethoxy)-phenyl]-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl}-N-hydroxyacetamido (5.45)

SynthesisMethodNameStructure
164N2-{2-[4-(2-Dimethylaminoethoxy)-phenyl]-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl}-N-hydroxyacetamido (5.46)
165N2-[2-(4-Allyloxyphenyl)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]-N-hydroxyacetamido (5.47)
166N2-{1,1-dio is with-2-[4-(pyridine-4-ylethoxy)phenyl]-2,3-dihydro-1H-benzo[d]isothiazol-3-yl}-N-hydroxyacetamido (5.48)
167N2-{1,1-Dioxo-2-[4-(pyridine-3-ylethoxy)phenyl]-2,3-dihydro-1H-benzo[d]isothiazol-3-yl}-N-hydroxyacetamido (5.49)
168N2-{1,1-Dioxo-2-[4-(pyridine-2-ylethoxy)phenyl]-2,3-dihydro-1H-benzo[d]isothiazol-3-yl}-N-hydroxyacetamido (5.50)

SynthesisMethodNameStructure
169I2-{2-[4-(4-Hydroxy-but-2-ynyloxy)-phenyl]-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl}-N-hydroxyacetamido (5.51)
170G2-[1,1-Dioxo-2-(4-Penta-2-injectively)-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]-N-hydroxyacetamido (5.52)
171G2-[1,1-Dioc the o-2-(4-prop-2-ynyloxy-phenyl)-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]-N-hydroxyacetamido (5.53)
172N2-[2-(4-but-3-enyloxy-phenyl)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]-N-hydroxyacetamido (5.54)
173G2-[2-(4-but-3-enyloxy-phenyl)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]-N-hydroxyacetamido (5.55)

SynthesisMethodNameStructure
174N2-(2-{4-[1-(2-Methylinosine-4-yl)ethoxy]-phenyl}-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)-N-hydroxyacetamido (5.56)
175N2-{1,1-Dioxo-2-[4-quinoline-4-ylethoxy)phenyl]-2,3-dihydro-1H-benzo[d]isothiazol-3-yl}-N-hydroxyacetamido (5.57)
176N2-{2-[4-(6-Fluoro--methyl-quinoline-4-ylethoxy)-phenyl]-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl}-N-hydroxyacetamido (5.58)
177N2-{2-[4-(6-Chloro-2-methylinosine-4-ylethoxy)-phenyl]-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl}-N-hydroxyacetamido (5.59)
178N2-{2-[4-(2-Methylpyridin-4-ylethoxy)-phenyl]-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl}-N-hydroxyacetamido (5.60)

SynthesisMethodNameStructure
179N2-{2-[4-(2,6-Dimethylpyridin-4-ylethoxy)phenyl]-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl}-N-hydroxyacetamido (5.61)
180G2-(5-Methoxy-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)-N-hydroxyacetamido (5.62)
181G
182G2-(5,6-Dimethoxy-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)-N-hydroxyacetamido (5.64)
183N2(5,6,7-Trimetoksi-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)-N-hydroxyacetamido (5.65)

N
SynthesisMethodNameStructure
184N2-(5,7-Dimethoxy-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)-N-hydroxyacetamido (5.66)
185N2-(6-Methyl-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)-N-hydroxyacetamido (5.67)
1862-(6-Bromo-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)-N-hydroxyacetamido (5.68)

Connection (5.1): Yield 85%, melting point 141-143°C,1H-NMR (DMSO-d6) TMS) δ: 2.32 (1H, dd, 9 Hz and 15 Hz); 2.64 (1H, dd, 4 Hz and 15 Hz); 5.73 (1H, dd, 4 Hz and 9 Hz); 7.2-7.4 (1H, m); 7.4-7.6 (4H, m); 7.6-7.9 (3H, m); 7.98 (1H, d, 8 Hz); 8.9 (1H, br s) and 10.5 ppm (1H, brs).

Connection (5.2): Output 12%, amorphous,1H-NMR (DMSO-d6, TMS) δ: 2.39 (1H, dd, 15 Hz and 9 Hz); 2.69 (1H, dd, 15 Hz and 4 Hz); 5.84 (1H, dd, 8 Hz and 4 Hz); 7.5-8.1 (11N, m); 8.89 (1H, s), and 10.49 ppm (1H, s).

Connection (5.3): Yield 45%, amorphous,1H-NMR (DMSO-d6, TMS) δ: 2.29 (1H, dd, 9 Hz and 15 Hz); 2.35 (3H, s); 2.63 (1H, dd, 4 Hz and 15 Hz); 5.67 (1H, dd, 4 Hz and 9 Hz); 7.15 (1H, d, 7 Hz); 7.2-7.9 (6N, m); 7.97 (1H, d, 8 Hz); 8.94 (1H, br s) and 10.52 ppm (1H, br s).

Connection (5.4): Output 12%, amorphous,1H-NMR (DMSO-d6, TMS) δ: 2.30 (1H, dd, 8 Hz and 15 Hz); 2.58 (1H, dd, 4 Hz and 15 Hz); 5.60 (1H, dd, 4 Hz and 8 Hz); 7.29 (2H, d, 8 Hz); 7.37 (2H, d, 8 Hz); 7.6-7.9 (3H, m); 7.96 (1H, d, 8 Hz); 8.92 (1H, br s) and 10.51 ppm (1H, br s).

The compound (5.5): Yield 86%, amorphous,1H-NMR (DMSO-d6, TMS) δ: 2.1-2.6 (5H, m); 5.34 (1H, t, 7 Hz); 7.2-7.9 (7H, m); 7.97 (1H, d, 8 Hz); 8.90 (1H, br s) and 10.55 ppm (1H, br s).

Connection (5.6): Yield 62%, amorphous,1H-NMR (DMSO-d6, TMS) δ: 2.34 (1H, dd, 15 Hz and 8 Hz); 2.4-2.6 (1H, overlap with DMSO); 3.76 (3H, s); 5.49 (1H, dd, 8 Hz and 5 Hz); 7.05 (1H, t, 7 Hz); 7.19 (1H, d, 8 Hz); 7.4-7.9 (5H, m); 7.95 (1H, d, 7 Hz); 8.86 (1H, s) and 10.51 ppm (1H, s).

Connection (5.7): O the d 62%, the melting point 147-148°C,1H-NMR (DMSO-d6, TMS) δ: 2.31 (1H, dd, 15 Hz and 9 Hz); 2.66 (1H, dd, 15 Hz and 4 Hz); 3.79 (3H, s); 5.71 (1H, dd, 9 Hz and 4 Hz); 6.91 (1H, d, 7 Hz); 7.05 (1H, s); 7.07 (1H, d, 7 Hz); 7.45 (1H, t, 8 Hz); 7.6-7.8 (3H, m); 7.98 (1H, d, 7 Hz); 8.93 (1H, s), 10.52 ppm (1H, s).

Connection (5.8): 51%Yield, melting point 185-186°C,1H-NMR (DMSO-d6, TMS) δ: 2.33 (1H, dd, 15 Hz and 8 Hz); 2.5-2.6 (1H, overlap with DMSO); 3.80 (1H, s); 5.47 (1H, dd, 8 Hz and 4 Hz); 7.05 (2H, d, 9 Hz); 7.43 (2H, d, 9 Hz); 7.6-7.9 (3H, m); 7.94 (1H, d, 8 Hz); 8.89 (1H, s), 10.50 ppm (1H, s).

Connection (5.9): Yield 54%, melting point 181-182°C,1H-NMR (DMSO-d6, TMS) δ: 2.34 (1H, dd, 15 Hz and 8 Hz); 2.68 (1H, dd, 15 Hz and 4 Hz); 5.73 (1H, dd, 9 Hz and 4 Hz); 6.88 (1H, d, 8 Hz); 7.0-7.9 (11N, m); 7.97 (1H, d, 8 Hz); 8.93 (1H, s) and 10.51 ppm (1H, s).

Connection (5.10): Output 10%, the melting point of 184-185°C,1H-NMR (DMSO-d6, TMS) δ: 2.36 (1H, dd, 14 Hz and 8 Hz); 2.62 (1H, dd, 14 Hz and 8 Hz); 5.72 (1H, dd, 8 Hz and 4 Hz); 7.50 (2H, d, 8 Hz); 7.57 (2H, d, 8 Hz); 7.6-7.9 (3H, m); 7.99 (1H, d, 7 Hz); 8.89 (1H, s), and 10.49 ppm (1H, s).

Connection (5.11): Yield 53%, amorphous,1H-NMR (DMSO-d6, TMS) δ: 2.33 (1H, dd, 15 Hz and 8 Hz); approximately 2.5 (3H, overlap with DMSO); 2.65 (1H, dd, 15 Hz and 4 Hz); 5.75 (1H, dd, 8 Hz and 4 Hz); 7.2-7.9 (7H, m); 7.98 (1H, d, 8 Hz); 8.93 (1H, s) and 10.51 ppm (1H,s).

Connection (5.12): Output 12%, amorphous,1H-NMR (DMSO-d6, TMS) δ: 2.40 (1H, dd, 15 Hz and 8 Hz); 2.66 (1H, dd, 15 Hz and 4 Hz); 5.90 (1H, dd, 8 Hz and 4 Hz); 7.6-7.9 (7H, m); 8.01 (1H, d, 7 Hz); 8.89 (1H, s) and 10.51 ppm (1H, s).

Connection (5.13): Exit 19%, amorphous,1H-NMR (DMSO-d6, TMS) δ: 2.36 (1H, dd 15 Hz and 8 Hz); 2.67 (1H, dd, 15 Hz and 4 Hz); 5.84 (1H, dd, 8 Hz and 4 Hz); 7.31 (1H, d, 8 Hz); 7.4-7.9 (1H, m); 8.00 (1H, d, 8 Hz); 8.92 (1H, s) and 10.51 ppm (1H, s).

Connection (5.14): Exit 27%, amorphous,1H-NMR (DMSO-d6, TMS) δ: 2.36 (1H, dd, 8 Hz and 15 Hz); 2.62 (1H, dd, 4 Hz and 15 Hz); 5.70 (1H, dd, 4 Hz and 8 Hz); 7.27 (2H, d, 8 Hz); 7.6-7.9 (5H, m); 7.97 (1H, d, 8 Hz); 8.89 (1H, br s) and 10.48 ppm (1H, br s).

Connection (5.15): Yield 37%, amorphous,1H-NMR (DMSO-d6, TMS) δ: 2.37 (1H, dd, 15 Hz and 8 Hz); 2.70 (1H, dd, 15 Hz and 4 Hz); 5.83 (1H, dd, 8 Hz and 4 Hz); 7.5-7.8 (N, m); 7.98 (1H, d, 7 Hz); 8.91 (1H, s), 10.52 ppm (1H, s).

Connection (5.16): Yield 52%, amorphous,1H-NMR (DMSO-d6, TMS) δ: 2.36 (1H, dd, 15 Hz and 8 Hz); 2.56 (1H, dd, 15 Hz and 4 Hz); 5.60 (1H, dd, 8 Hz and 4 Hz); 7.33 (2H, t, 9 Hz); 7.52 (2H, dd, 9 Hz and 5 Hz); 7.61 - 7.83 (3H, m); 7.96 (1H, d, 7 Hz); 8.86 (1H, s), 10.48 ppm (1H, s).

Connection (5.17): Exit 22%, amorphous,1H-NMR (DMSO-d6, TMS) δ: 2.36 (1H, dd, 15 Hz and 9 Hz); 2.73 (1H, dd, 15 Hz and 4 Hz); 5.93 (1H, dd, 9 Hz and 4 Hz); 7.54-7.90 (7H, m); 8.03 (1H, d, 8 Hz); 8.94 (1H, s), 10.52 ppm (1H, s).

Connection (5.18): the melting point of 178-179°C,1H-NMR (DMSO-d6, TMS) δ: 2.37 (1H, dd, 15 Hz and 8 Hz); 2.64 (1H, dd, 15 Hz and 4 Hz); 5.75 (1H, dd, 8 Hz, 4 Hz); 7.50-7.83 (7H, m); 8.00 (1H, d, 8 Hz); 8.91 (1H, s) and 10.51 ppm (1H, s).

Connection (5.19): Exit 9%, amorphous,1H-NMR (DMSO-d6, TMS) δ: 2.32 (1H, dd, 14.7 Hz and 8.8 Hz); 2.70 (1H, dd, 14.7 Hz and 3.9 Hz); 5.86 (1H, dd, 8.8 Hz and 3.9 Hz); 7.5-7.9 (7H, m); 8.00 (1H, d, 7.8 Hz), 8.96 (1H, s) and 10.54 ppm (1H, s).

Connection (5.20): Yield 85%, melting point 197-198°C (dec.)1H-NMR (DMSO-d6, TMS) δ: 2.32 (1H, dd, 8.8 and 14.7 Hz); 2.49 (3H, s); 2.59 (1H,dd, 4.4 and 14.7); 5.61 (1H, dd, 4.4 and 8.1 Hz); 7.39 (2H, d, 8.8 Hz); 7.42 (2H, d, 8.8 Hz); 7.5-7.9 (3H, m); 7.95 (1H, d, 8.1 Hz); 8.89 (1H, s), and 10.49 ppm (1H, s).

Connection (5.21): Yield 48% amorphous,1H-NMR (DMSO-d6, TMS) δ: 1.19 (3H, t, 7.3 Hz); 2.28 (1H, dd, and 14.7 8.8 Hz); 2.5-2.7 (1H, m overlapping with DMSO); 2.62 (2H, q, 8.1 Hz); 5.59 (1H, dd, 8.8 and 3.7 Hz); 7.31 (2H, d, 8.8 Hz); 7.39 (2H, d, 8.8 Hz); 7.5-7.9 (3H, m); 7.95 (1H, d, 7.3 Hz); 8.91 (1H, s), 10.50 ppm (1H, s).

Connection (5.22): Yield 42%, melting point 160-161°C,1H-NMR (DMSO-d6, TMS) δ: 1.23 (6N, d, 7 Hz); 2.29 (1H, dd, 15 Hz and 9 Hz); 2.62 (1H, dd, 15 Hz and 4 Hz); 2.93 (1H, m); 5.61 (1H, dd, 9 Hz, and 4 Hz); 7.34-7.44 (4H, m); 7.59-7.84 (3H, m); 7.97 (1H, d, 7 Hz); 8.95 (1H, s) and 10.53 ppm (1H, s).

Connection (5.23): Exit 27%, the melting point 207-208°C. (dec.),1H-NMR (DMSO-d6, TMS) δ: 2.2-2.9 (2H, m, overlapping with DMSO); 5.7-5.8 (1H, m); 7.3-7.9 (N, m); 7.99 (1H, d, 6.8 Hz); 8.93 (1H, s) and 10.53 ppm (1H, s).

Connection (5.24): Yield 47%, the melting point 174-175°C,1H-NMR (DMSO-d6, TMS) δ: 2.35 (1H, dd, 15 Hz and 8 Hz); 2.60 (1H, dd, 15 Hz and 4 Hz); 5.57 (1H, dd, 8 Hz and 4 Hz); 7.06-7.21 (5H, m); 7.38-7.52 (4H, m); 7.73-7.84 (3H, m); 7.97 (1H, d, 8 Hz); 8.91 (1H, s) and 10.51 ppm (1H, s).

Connection (5.25): Yield 86%, melting point, 186-187°C1H-NMR (DMSO-d6, TMS) δ: 2.32 (1H, dd, 15 Hz and 8 Hz); approximately 2.5 (1H, overlap with DMSO); 5.14 (2H, s); 5.48 (1H, dd, 8 Hz and 4 Hz); 7.13 (2H, d, 9 Hz); 7.37-7.82 (10H, m); 7.95 (1H, d, 8 Hz); 8.92 (1H, s), 10.52 ppm (1H, s).

Connection (5.26): Yield 47%, the melting point 192-194°C (dec.),1H-NMR (DMSO-d6, TMS) δ: 2.32-2.67 (2H, m, 1H, overlap with DMSO); 5.70 (1H, m); 6.29 (2H, s); 7.41 (2 is, s); 7.40-7.95 (7H, m); 7.98 (1H, d, 7 Hz); 8.91 (1H, s), 10.52 ppm (1H, s).

Connection (5.27): Exit 22%, the melting point 199-201°C (dec.),1H-NMR (DMSO-d6, TMS) δ: 2.34-2.63 (1H, m, overlapping with DMSO); 5.76 (1H, m); 7.13 (1H, s); 7.60-7.78 (8H, m); 7.99 (1H, d, 7.3 Hz); 8.29 (1H, s); 8.91 (1H, s), 10.55 ppm (1H, s).

Connection (5.28): Yield 60%, melting point 205-207°C (dec.),1H-NMR (DMSO-d6, TMS) δ: 2.41 (1H, dd, 14 Hz and 8 Hz); 2.67 (1H, dd, 14 Hz and 5 Hz); 5.80 (1H, dd, 8 Hz, 5 Hz); 7.65-7.87 (5H, m); 7.99 (2H, d, 9 Hz); 8.00 (1H, d, 7 Hz); 8.27 (1H, s); 8.90 (1H, s); 9.33 (1H, s)n 10.51 ppm (1H, s).

Connection (5.29): Exit 27%, the melting point 138-140°C (dec.),1H-NMR (DMSO-d6, TMS) δ: 2.37 (1H, dd, 15 Hz and 8 Hz); 2.68 (1H, dd, 15 Hz and 4 Hz); 5.81 (1H, dd, 8 Hz, 4 Hz); 7.56-7.87 (8H, m); 7.99 (1H, d, 7 Hz); 8.48 (1H, s); 8.92 (1H, s), 10.52 ppm (1H, s).

Connection (5.30): Exit 38%, the melting point 179-181°C (dec.),1H-NMR (DMSO-d6, TMS) δ: 2.37 (1H, dd, overlapping with DMSO); 2.71 (3H, s); 5.74 (1H, dd, 8.1 Hz and 3.7 Hz); 7.51 (2H, d, 8.8 Hz); 7.61 - 7.84 (3H, m); 7.95-8.05 (4H, m); 8.91 (1H, s) and 10.53 ppm (1H, s).

Connection (5.31): Yield 39%. Melting point: 185-186°C,1H-NMR (DMSO-d6, TMS) δ: 2.27 (1H, dd, 15 Hz and 9 Hz); ~2.5 (1H, overlap with DMSO); 2.94 (6N, s); 5.33 (1H, dd, 8 Hz and 4 Hz); 6.77 (2H, d, 9 Hz); 7.27 (2H, d, 9 Hz); 7.59-7.82 (3H, m); 7.92 (1H, d, 7 Hz); 8.92 (1H, s), 10.52 ppm (1H, s,).

Connection (5.32): Yield 61%, melting point 204-206°C,1H-NMR (DMSO-d6, TMS) δ: 2.29 (1H, dd, 15 Hz and 9 Hz); approximately 2.5 (1H, overlap with DMSO); 3.16 (4H, m); 3.75 (4H, m); 5.43 (1H, dd, 9 Hz and 4 Hz); 7.04 (2H, d, 9 Hz); 7.33 (2H, d, 9 Hz); 7.58-7.82 (3H, m); 7.94 (M, d, 7 Hz); 8.92 (1H, s), 10.52 ppm (1H, s).

Connection (5.33): Yield 60%, the melting point of 177-178°C,1H-NMR (DMSO-d6, TMS) δ: 1.35 (3H, t, 7 Hz); 2.31 (1H, dd, 15 Hz and 8 Hz); approximately 2.5 (1H, overlap with DMSO); 4.06 (2H, q, 7 Hz); 5.46 (1H, dd, 8 Hz, 4 Hz); 7.03 (2H, d, 9 Hz); 7.40 (2H, d, 9 Hz); 7.59-7.82 (3H, m); 7.97 (1H, d, 7 Hz); 8.89 (1H, s) and 10.51 ppm (1H, s).

Connection (5.34): Yield 63%, melting point 165-166°C,1H-NMR (DMSO-d6, TMS) δ: 0.94 (3H, t, 7 Hz); 1.39-1.50 (2H, m); 1.65-1.75 (2H, m); 2.28 (1H, dd, 15 Hz and 8 Hz); 2.55 (1H, dd, 15 Hz and 4 Hz); 4.00 (2H, t, 7 Hz); 5.47 (1H, dd, 8 Hz and 4 Hz); 7.04 (2H, d, 9 Hz); 7.39 (2H, d, 9 Hz); 7.60 - 7.82 (3H, m); 7.95 (1H, d, 7 Hz); 8.91 (1H, s) and 10.51 ppm (1H, s).

Connection (5.35): Yield 63%, amorphous,1H-NMR (DMSO-d6, TMS) δ: 2.33 (1H, dd, 15 Hz and 8 Hz); 2.56 (1H, dd, 15 Hz and 4 Hz); 4.82 (2H, q, 9 Hz); 5.54 (1H, dd, 8 Hz, 4 Hz); 7.18 (2H, d, 9 Hz); 7.46 (2H, d, 9 Hz); 7.61-7.84 (3H, m); 7.96 (1H, d, 7 Hz); 8.90 (1H, s) and 10.51 ppm (1H, s).

Connection (5.36): Exit 49% melting point 145-147°C (dec.),1H-NMR (DMSO-d6, TMS) δ: 2.34 (1H, dd, 8 Hz and 15 Hz); 2.66 (1H, dd, 4 Hz and 15 Hz); 5.77 (1H, dd, 4 Hz and 8 Hz); 7.1-7.3 (1H, m); 7.3-7.5 (2H, m); 7.5-7.9 (4H, m); 7.99 (1H, d, 7 Hz); 8.91 (1H, s), 10.55 ppm (1H, s).

Connection (5.37): Exit 7%, the melting point 152-154°C,1H-NMR (DMSO-d6, TMS) δ: 2.37 (1H, dd, 15 Hz and 9 Hz); 2.60 (1H, dd, 15 Hz and 6 Hz); 4.98 (1H, t, 7 Hz); 7.54-7.82 (3H, m); 7.80 (1H, d, 9 Hz); 8.80 (1H, br s); 8.92 (1H, br s) and 10.54 ppm (1H, s).

The compound (5.38): amorphous,1H-NMR (DMSO-d6, TMS) δ: approximately 2.5 (1H, overlap with DMSO); 2.67 (1H, dd, 15 Hz and 6 Hz); 2.79 (3H, s); 4.76 (1H, t, 6 Hz); 7.60-7.77 (3H, ); 7.87 (1H, d, 7 Hz); 8.90 (1H, s), 10.65 ppm (1H, s).

Connection (5.39): Yield 55%, amorphous,1H-NMR (DMSO-d6, TMS) δ: 2.32 (1H, dd, 15 Hz and 8 Hz); 2.71 (1H, dd, 15 Hz and 6 Hz); 4.37 (1H, d, 15 Hz); 4.63 (1H, d, 15 Hz); 4.81 (1H, dd, 8 Hz and 6 Hz); 7.23-7.51 (6N, m); 7.51-7.75 (2H, m); 7.91 (1H, d, 8 Hz); 8.98 (1H, s), 10.61 ppm (1H, s).

Connection (5.40): Exit 39% melting point 189-190°C,1H-NMR (DMSO-d6, TMS) δ: 2.40-2.62 (2H, m, overlapping with DMSO); 3.89 (3H, s); 5.51 (1H, t, 6 Hz); 6.96 (1H, d, 8 Hz); 7.67-7.88 (4H, m); 7.98 (1H, d, 8 Hz); 8.24 (1H, d, 2 Hz); 8.85 (1H, s), 10.50 ppm (1H, s).

Connection (5.41): Yield 58%, amorphous,1H-NMR (DMSO-d6, TMS) δ: 0.94-2.36 (10H, m); 2.31 (1H, dd, 14.7 Hz and 8.1 Hz); 2.72 (1H, dd, 14.7 Hz, 5.9 Hz); 3.42-3.54 (1H, m); 5.06 (1H, dd, 8.1 Hz, 5.1 Hz); 7.47-7.71 (3H, m); 7.79 (1H, d, 8.1 Hz); 8.95 (1H, s) and 10.57 ppm (1H, s).

The compound (5.42): Yield 58%, melting point 141-143°C,1H-NMR (DMSO-d6, TMS) δ: 1.7-2.1 (6N, m); 2.30 (1H, dd, 8.1 Hz, 14.7 Hz); 2.69 (1H, dd, 5.1 Hz, 14.7 Hz); 2.8-3.0 (2H, m); 3.44 (2H, s); 3.3.2-3.6 (1H, m); 5.05 (1H, dd, 5.9 and 7.3 Hz); 7.2 - 7.4 (5H, m); 7.4-7.7 (3H, m); 7.78 (1H, d,, 8.1 Hz); 8.96 (1H, s) and 10.57 ppm (1H, s).

Connection (5.43): Yield 25%, amorphous,1H-NMR (DMSO-d6, TMS) δ: 1.84 (3H, s); 2.30 (1H, dd, 14 Hz and 7 Hz); 2.5-2.6 (1H, overlap with DMSO); 4.77 (2H, d, 2 Hz); 5.47 (1H, dd, 8 Hz and 4 Hz); 7.06 (2H, d, 9 Hz); 7.40 (2H, d, 9 Hz); 7.5-7.8 (3H, m); 7.94 (1H, d, 7 Hz); 8.89 (1H, s), 10.50 ppm (1H, s).

Connection (5.44): Yield 31%, melting point 195-197°C,1H-NMR (DMSO-d6, TMS) δ: 2.1-2.6 (2H, m); 2.68 (3H, s); 5.4-5.6 (1H, m); 5.65 (2H, s); 7.28 (2H, d, 9 Hz); 7.47 (2H, d, 9 Hz); 7.5-7.9 (6N, m); 7.9-8.1 (2H, m); 8.13 (1H, d, 7 Hz); 8.90 (1H, s), 10.52 ppm (1 is, s).

The compound (5.45): Exit 14%, amorphous,1H-NMR (DMSO-d6, TMS) δ: 2.1-2.6 (2H, m); 2.21 (6N, s); 2.62 (2H, t, 6 Hz); 4.07 (2H, t, 6 Hz); 5.45 (2H, dd, 4 and 8 Hz); 7.04 (2H, d, 9 Hz); 7.39 (2H, d, 9 Hz); 7.5-7.9 (3H, m); 7.94 (1H, d, 7 Hz); 8.91 (1H, br. s) and 10.50 ppm (1H, br. s).

The compound (5.46): Yield 30%, amorphous,1H-NMR (DMSO-d6, TMS) δ: 2.1-2.6 (2H, m); 2.21 (6N, s); 2.62 (2H, t, 6 Hz); 4.07 (2H, t, 6 Hz); 5.45 (2H, dd, 4 and 8 Hz); 7.04 (2H, d, 9 Hz); 7.39 (2H, d, 9 Hz); 7.5-7.9 (3H, m); 7.94 (1H, d, 7 Hz); 8.91 (1H, br. s) and 10.50 ppm (1H, br. s).

Connection (5.47): Yield 55%, melting point 166-168°C (dec.),1H-NMR (DMSO-d6, TMS) δ: 2.34-2.63 (2H, m, overlapping with DMSO); 4.59 (2H, d, 5.1 Hz); 2.29 (2H, dt, 13.9 Hz, 1.5 Hz); 5.45 (1H, dd, 7.8 Hz, 2.9 Hz); 5.95-6.14 (1H, m); 7.04 (2H, dd, 8.8 Hz, 2.0 Hz); 7.38 (2H, dd, 8.8 Hz, 2.0 Hz); 7.61-7.96 (4H, m); 8.89 (1H, s); 10.50 ppm (1H, s).

The compound (5.48): melting Point 212-214°C (dec.),1H-NMR (DMSO-d6, TMS) δ: 2.2-2.7 (2H, m, overlapping with DMSO); 5.23 (2H, s); 5.4-5.6 (1H, m); 7.14 (2H, d, 8.8 Hz); 7.35-7.55 (4H, m); 7.55-7.90 (3H, m); 7.95 (1H, d, 7.3 Hz); 8.59 (2H, d, 5.1 Hz); 8.91 (1H, br s) and 10.52 ppm (1H, s).

Connection (5.49): Amorphous powder,1H-NMR (DMSO-d6, TMS) δ: 2.2-2.6 (2H, m, overlapping with DMSO); 5.33 (2H, s); 5.4-5.6 (1H, m); 7.17 (2H, d, 8.8 Hz); 7.45 (2H, d, 8.8 Hz); 7.5-7.9 (3H, m); 7.9-8.1 (2H, m); 8.58 (1H, d, 8.1 Hz); 8.8-8.9 (1H, m); 8.9-9.1 (1H, m) and 10.55 ppm (1H, s).

The compound (5.50): melting Point: 170°C (dec.),1H-NMR (DMSO-d6, TMS) δ: 2.2-2.6 (2H, m, overlapping with DMSO); 5.21 (2H, s); 5.4-5.6 (1H, m); 7.14 (2H, d, 8.8 Hz); 7.41 (2H, d, 8.8 Hz); 7.3-8.0 (7H, m); 8.58 (1H, d, 4.4 Hz); 8.89 (1H, s), and 10.49 ppm (1H, s).

Link is (5.51): Exit 23%, amorphous,1H-NMR (DMSO-d6, TMS) δ: 2.50-2.56 (2H, m, overlapping with DMSO); 4.11 (2H, d, 5.8 Hz); 4.86 (2H, s); 5.25 (1H, t, 5.8 Hz); 5.48 (1H, dd, 8.4 Hz and 4.4 Hz); 7.09 (2H, dd, 8.7 Hz and 1.8 Hz); 7.43 (2H, dd, 9.1 Hz and 2.2 Hz); 7.62 (1H, d, 8.0 Hz); 7.69 (1H, t, 7.3 Hz); 7.79 (1H, t, 7.3 Hz); 7.95 (1H, d, 8.0 Hz); 8.89 (1H, s), 10.50 ppm (1H, s).

Connection (5.52): Exit 7%, melting point, 135-137°C (dec.),1H-NMR (DMSO-d6, TMS) δ: 2.22-2.26 (2H, m); 2.36-2.58 (2H, m, overlapping with DMSO); 4.78 (2H, d, 2.0 Hz); 5.48 (1H, dd, 7.8 Hz, 2.9 Hz); 7.08 (2H, dd, 8.8 Hz, 2.0 Hz); 7.42 (2H, dd, 8.8 Hz, 2.0 Hz); 7.59-7.97 (4H, m); 8.90 (1H, s); 10.51 ppm (1H, s).

The compound (5.53): the Yield of 2%, the melting point 155-157°C (dec.),1H-NMR (DMSO-d6, TMS) δ: 2.37-2.59 (3H, m, overlapping with DMSO); 4.85 (2H, d, 2.2 Hz); 5.50 (1H, dd, 7.8 Hz, 2.9 Hz); 7.14 (2H, dd, 8.8 Hz, 2.0 Hz); 7.44 (2H, dd, 8.8 Hz, 2.0 Hz); 7.61-7.99 (4H, m); 8.91 (1H, s); 10.52 ppm (1H, s).

The compound (5.54): Yield 64%, the melting point 148-150°C (dec.),1H-NMR (DMSO-d6, TMS) δ: 2.30-2.50 (1H, m, overlapping with DMSO); 2.50-2.68 (3H, m, overlapping with DMSO); 4.10 (2H, t, 5.9 Hz); 5.50 (1H, dd, 7.8 Hz and 2.9 Hz); 7.06 (2H, dd, 8.8 Hz and 1.95 Hz); 7.40 (2H, dd, 8.8 Hz and 1.95 Hz); 7.59-7.97 (4H, m); 8.89 (1H, s), 10.50 ppm (1H s).

The compound (5.55): Yield 75%, the melting point of 152-154°C (dec.),1H-NMR (DMSO-d6, TMS) δ: 1.55 (3H, d, 5.9 Hz); 1.82 (3H, s); 2.30-2.50 (2H, m, overlapping with DMSO); 5.00-5.20 (1H, m); 5.50 (1H, dd, 7.8 Hz and 2.9 Hz); 7.08 (2H, dd, 8.8 Hz and 1.95 Hz); 7.41 (2H, dd, 8.8 Hz and 1.95 Hz); 7.60-7.98 (4H, m); 8.91 (1H, s), 10.52 ppm (1H, s).

Connection (5.56): Output 10%, the melting point 200-204°C (dec.),1H-NMR (DMSO-d6, TMS) δ: 1.70 (3, d, 5.8 Hz); 2.1-2.6 (2H, m, overlapping with DMSO); 2.63 (3H, s); 5.3-5.5 (1H, m); 6.2-6.4 (1H, s); 7.05 (2H, d, 8.8 Hz); 7.34 (2H, d, 8.8 Hz); 7.4-7.9 (6N, m); 7.9-8.1 (2H, m); 8.33 (1H, d, 8.0 Hz); 8.90 (1H, s), and 10.49 ppm (1H, s).

Connection (5.57): Yield 36%, the melting point 218-220°C (dec.),1H-NMR (DMSO-d6, TMS) δ: 2.2-2.7 (2H, m); 5.4-5.6 (1H, m); 5.71 (2H, s); 7.27 (2H, d, 8.8 Hz); 7.46 (2H, d, 8.8 Hz); 7.5-7.9 (6N, m); 7.96 (1H, d, 7.3 Hz); 8.09 (1H, d, 8.8 Hz); 8.20 (1H, d, 8.0 Hz); 8.89 (1H, s); 8.93 (1H, d, 4.4 Hz) and 10.51 ppm (1H, s).

Connection (5.58): Exit 18%, melting point: more than 140°C (dec.),1H-NMR (DMSO-d6, TMS) δ: 2.32 (1H, dd, 8.7 and 14.6 Hz, partial overlap with DMSO); 2.66 (3H, s); 5.51 (1H, dd, 3.7 and 8.1 Hz); 5.60 (2H, s); 7.28 (2H, d, 8.8 Hz); 7.46 (2H, d, 8.8 Hz); 7.5-7.8 (5H, m); 7.8-8.1 (3H, m); 8.89 (1H, s), and 10.49 ppm (1H, s).

Connection (5.59): melting Point 215°C (dec.),1H-NMR (DMSO-d6, TMS) δ: 2.2-2.7 (2H, m, overlapping with DMSO); 2.67 (3H, s); 4.9-5.6 (1H, m); 5.63 (2H, s); 7.20 (2H, d, 8.8 Hz); 7.46 (2H, d, 8.8 Hz); 7.5-7.9 (5H, m); 7.9-8.1 (2H, m); 8.22 (1H, d, 1.9 Hz); 8.88 (1H,8), and 10.50 ppm (1H s).

The compound (5.60): Yield 76%, melting point greater than 204°C (dec.),1H-NMR (DMSO-d6, TMS) δ: 2.30 (1H, dd, 8.1, and 14.7 Hz), 2.4-2.6 (1H, partially overlapping with DMSO); 3.29 (3H, s, overlapping with DMSO, H20); 5.16 (2H, s); 5.47 (1H, dd, 4.4 and 8.8 Hz); 7.12 (2H, d, 8.8 Hz); 7.23 (1H, d, 4.4 Hz); 7.31 (1H, s); 7.41 (2H, d, 8.8 Hz); 7.5-7.8 (3H, m); 7.93 (1H, d, 7.3 Hz); 8.43 (1H, d, 5.1 Hz); 8.88 (1H, d, 1.5 Hz) and 10.48 ppm (1H, s).

Connection (5.61): Yield 78%, the melting point greater than 210°C (dec.)1H-NMR (DMSO-d6, TMS) δ: 2.32 (1H, dd, 8.8 and 14.7 Hz), 2.43 (6N, s, overlapping with DMSO); 2.4-2.7 (1H partial overlap with DMSO); 5.12 (2H, s); 5.49 (1H, dd, 3.7 and 8.1 Hz); 7.0-7.2 (4H, m); 7.43 (2H, d, 8.8 Hz); 7.5-7.9 (3H, m); 7.95 (1H, d, 7.3 Hz); 8.89 (1H, s), 10.50 ppm (1H, s).

The compound (5.62): Yield 68%, the melting point of 180-182°C,1H-NMR (DMSO-d6, TMS) δ: 2.34 (1H, dd, 9 Hz and 15 Hz); 2.62 (1H, dd, 4 Hz and 15 Hz); 5.62 (1H, dd, 4 Hz and 9 Hz); 7.11 (1H, s); 7.2-7.6 (6N, m); 7.89 (1H, d, 9 Hz); 8.96 (1H, s) and 10.53 ppm (1H, s).

The compound (5.63): melting Point 202-204°C (dec.),1H-NMR (DMSO-d6, TMS) δ: 2.23 (1H, dd, 9 Hz and 15 Hz); 2.4-2.7 (1H, m, overlapping with DMSO); 4.33 (4H, m); 5.52 (1H, dd, 4 Hz and 9 Hz); 7.04 (1H, s); 7.2-7.6 (6N, m); 8.93 (1H, s), 10.50 ppm (1H, s).

The compound (5.64): melting Point 197-199°C (dec.),1H-NMR (DMSO-d6, TMS) δ: 2.2-2.7 (2H, m, overlapping with DMSO); 3.84 (3H, s); 3.86 (3H, s); 5.55 (1H, dd, 4 Hz and 9 Hz); 7.07 (1H, s); 7.2-7.4 (1H, m); 7.4-7.6 (5H, m); 8.94 (1H, s), 10.52 ppm (1H, s).

Connection (5.65): Yield 68%, amorphous,1H-NMR (DMSO-d6, TMS) δ: 2.2-2.7 (2H, m, overlapping with DMSO); 3.82 (3H, s); 3.89 (3H, s); 4.00 (3H, s); 5.51 (1H, dd, 3.7 Hz and 8.1 Hz); 6.90 (1H, s); 7.2-7.6 (6N, m); 8.93 (1H, s) and 10.51 ppm (1H, s).

The compound (5.66): Yield 75%, amorphous,1H-NMR (DMSO-d6, TMS) δ: 2.2-2.7 (2H, m, overlapping with DMSO); 3.86 (3H, s); 3.93 (3H, s); 5.52 (1H, dd, 3.7 Hz and 8.1 Hz); 6.63 (1H, s); 6.77 (1H, s); 7.3-7.6 (5H, m); 8.92 (1H, d, 1.5 Hz) and 10.50 ppm (1H, d, 1.5 Hz).

The compound (5.67): Yield 46%, amorphous,1H-NMR (DMSO-d6, TMS) δ: 2.27 (1H, dd, 14.7 Hz, 9.5 Hz); 2.45 (3H, s); 2.61 (1H, dd, 14.7 Hz, 3.7 Hz); 5.64 (1H, dd, 9.5 Hz, 3.7 Hz); 7.27-7.38 (1H, m); 7.44-7.54 (5H, m); 7.61 (1H, d, 8.1 Hz); 7.79 (1H, s); 8.93 (1H, s) and 10.53 ppm (1H, s).

The compound (5.68): Exit 38%, melting point 182-183 is C, 1H-NMR (DMSO-d6, TMS) δ: 2.33 (1H, dd, 8.8 Hz and 14.6 Hz); 2.65 (1H, dd, 3.7 Hz and 14.6 Hz); 5.65 (1H, dd, 3.7 and 8.1 Hz); 7.2-7.6 (5H, m); 7.58 (1H, d, 8.1 Hz); 7.78 (1H, d, 8.1 Hz); 8.31 (1H, s); 8.89 (1H, s), 10.48 ppm (1H, s).

Synthesis 187

Ethyl ester of 1-(2-methyl-quinoline-4-yl)methanesulfonic acid (15.12)

The solution hydroxymethylcytosine (17) (1.7 g, 10 mmol) in DCM (5 ml) was cooled in an ice bath and then added to 0.39 M solution periodinane on Dess-Martin in DCM (31 ml, 12 mmol). The resulting solution was stirred under cooling for 1.5 h and then added an aqueous solution of NaHCO3(15 ml). The mixture was stirred until then, until the organic and aqueous phase were not homogeneous. The organic phase is washed with aqueous Na2S2O3and saturated saline and dried over Na2SO4. The extract was filtered and the solvent was removed under vacuum. The residue was purified by flash chromatography on silica gel, elwira a mixture of light petroleum ether and EtOAc (2:1, 1:1) with the formation of crystalline material (0.51 g). It was dissolved in THF (10 ml) and cooled in an ice bath. Dropwise while cooling was added a 1.4 M solution MeMrBr in THF (4.3 ml, 6 mmol). The mixture was stirred for 30 minutes while cooling and then thereto was added saturated aqueous NH4Cl (50 ml) and water (50 ml). The mixture was extracted with EtOAc (100+50 ml). The combined organic phase was washed asystem salt solution (50 ml), dried over Na 2SO4, was filtered and was evaporated. The residue was purified by flash chromatography on silica gel, elwira a mixture of light petroleum ether and EtOAc(1:1, 1:0), with the formation of crystalline material (0,325 g). This product (300 mg) was dissolved in DCM (5 ml) and the solution was cooled in an ice bath. To him one of these portions was added triethylamine (0.45 ml, 3.2 mmol)and then dropwise added methylchloride (0.25 ml, 3.2 mmol). The cooling bath was set aside and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was diluted with DCM (30 ml) and washed with saturated brine (2×30 ml). The organic phase was dried over Na2SO4, was filtered and was evaporated to education (5.12) (0,47 g) as a crude product.

Synthesis 188

Hydrochloric salt of 4-chloromethylpyridine (15.13)

Chloride thionyl (1,45 ml, 20 mmol) was added dropwise to a solution of the carbinol (18) (1.5 g, 9.4 mmol) in DCM at room temperature. The reaction mixture was stirred at room temperature for 1 h and evaporated to education (15.13) (2.0 g) as a crude product.

General procedure for the synthesis of chloromethylene (15.14) and (15.15)

Method J: quinoline-carboxylic acid (19.1) and (19.2) (4 mmol) was boiled under reflux in a mixture of Meon (13 ml) and H2O4(2.5 ml) for 3 h, the Reaction mixture is cooled is about room temperature and to it was added water (25 ml). Was added saturated aqueous NaHCO3in order to adjust the pH to approximately 8. The mixture was extracted with EtOAc (2×35 ml). The combined organic phase was dried over Na2SO4, was filtered and was evaporated with the formation of the crude ether complex. It was dissolved in (25 ml) and portions were added NaBH4(0,76 g, 20 mmol), thereby to maintain a low boil. After the addition, the reaction mixture was stirred for 1 h at room temperature and added to water (100 ml). The reaction mixture was extracted with EtOAc (100 ml), washed with saturated saline (50 ml) and dried over Na2SO4. The extract was filtered and evaporated to education hydroxymethylcellulose derived. It was dissolved in DCM (30 ml) and to the solution was added dropwise chloride thionyl (of 0.47 ml, 6.4 mmol). The reaction mixture is boiled under reflux for 3 h and evaporated to education (15.14) and (15.15) as a crude product.

Following the method similar to Method J, were obtained connection in the form of the crude product.

SynthesisMethodNameStructure
189JChlorine is estomatologia salt of 4-chloromethyl-6-fluoro-2-methylinosine (15.14)
190JHydrochloric salt of 4-chloromethyl-6-chloro-2-methylinosine (15.15)

General procedure for the synthesis of chloromethylpyridine (15.16) and (15.17)

Method K: a Solution of 4-methylpyridine derived (20.1) and (20.2) (40 mmol) in dry THF was cooled to -70°C in an inert atmosphere, and thereto was added dropwise 1.6 M n-BuLi in hexano (28 ml, 44 mmol). After complete addition, the solution was further stirred for another 30 minutes at -70°C. was added DMF (6.2 ml, 80 mmol). The mixture was additionally stirred for 1 h 30 min at -70°C and "extinguished" saturated aqueous NH4Cl (10 ml) and was heated to room temperature. The mixture was partially evaporated, to the residue was added water (100 ml) and was extracted with CHCl3(3×100 ml). The combined organic phase was washed with saturated saline (100 ml), dried over Na2SO4filtered and evaporated. The residue was dissolved in Meon (30 ml) and to the suspension was added dropwise NaIO4(25,7 g, 120 mmol) in Meon (30 ml) at such a rate as to maintain a low boil. The mixture was passed through a short zletovo column and to the solution was added NaBH4(4,54 g, 120 mmol). The mixture was stirred for 30 min and was added n is a significant amount of SiO 2. The solvent was removed under vacuum, and the residue was applied onto silicagel column. Elution DCM containing 5% Meon, led to hydroxymethylbilane (20.1) and (20.2). The intermediate compound (20.1) and (20.2) (7 mmol) was dissolved in DCM (70 ml), and to the solution was added dropwise chloride thionyl (1,05 ml, 14.4 mmol). The reaction mixture is boiled under reflux for 3 h and evaporated to education (15.16) and (15.17) in the form of a crude product.

Following methods similar to Method J, were obtained the following compounds in the form of a crude product.

SynthesisMethodNameStructure
191KHydrochloric salt of 4-chloromethyl-2-methylpyridine (15.16)
192KHydrochloric salt of 4-chloromethyl-2,6-dimethylpyridine (15.17)

Synthesis 193

2-(1,1-Dioxo-2-(3-hydroxymethylene)-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)-N-hydroxyacetamido (24)

Sodium chlorite is also sulfonyl (1.1) (2 mmol) and 3-hydroxymethylbilane (22) (2 mmol) in dioxane (10 ml) was added 1 M aqueous solution of NaHCO 3(4 ml). The resulting mixture was stirred at room temperature for 2 hours and was diluted with water (50 ml). The precipitate was collected on a filter, washed with water and vacuum dried over P2O5receiving ester (23) (427 mg, 62%). To a solution of ester (23) (174 mg, 0.5 mmol) in methanol (2 ml) was added a solution of hydrochloric salt of hydroxylamine (174 mg, 2.5 mmol) and KOH (278 mg, 4 mmol) in methanol (3 ml). The mixture was left overnight to mix at room temperature and was evaporated. To the residue was added water and then 20% KHSO4to achieve a neutral pH. The mixture was extracted with ethyl acetate (20 ml). The organic phase was separated, washed with saturated saline (20 ml) and dried over Na2SO4. The solution was filtered and evaporated. The residue was treated with acetonitrile, the precipitate was collected on a filter and dried, obtaining (24) (15 mg, 9%), melting point 165-166°C,1H-NMR (DMSO-d6, TMS) δ: 2.29 (1H, dd, 9 Hz and 15 Hz); 2.63 (1H, dd, 4 Hz and 15 Hz); 4.54 (1H, d, 5 Hz); 5.34 (1H, t, 5 Hz); 5.67 (1H, dd, 4 Hz and 9 Hz); 7.2-7.8 (7H, m); 7.98 (1H, d, 8 Hz); 8.9 (1H, br s) and 10.5 ppm (1H, br s).

Synthesis 194

N-tert-Butoxycarbonyl-4-(4-nitrophenoxy)-but-2-enylamine (25)

A solution of alcohol (16.7) (278 mg, of 1.34 mmol) and triethylamine (0,37 ml, 2.68 mmol) in benzene (11 ml) was cooled in an ice bath in an argon atmosphere. To this solution was added methylchloride (of 0.21 ml, 2,68 IMO is b). The mixture was left to reach room temperature and was stirred for 2 hours It was filtered through a short silicagel column, elwira benzene. The solution was washed with saturated aqueous NaHCO3(50 ml) and saturated aqueous salt solution (50 ml), dried over Na2SO4and was evaporated. The residue (382 mg) was dissolved in DMF (11 ml) and NaN3(231 mg, 3,55 mmol). The reaction mixture was stirred for 4 days at room temperature and was diluted with water (30 ml). The mixture was extracted with Et2O (3×25 ml). The combined organic phase was washed with water (30 ml), dried over Na2SO4, and the solvent was removed under vacuum. The residue (311 mg) was dissolved in Et2O (10 ml)and the mixture was cooled in an ice bath. To it was added triphenylphosphine (352 mg, of 1.34 mmol) and the mixture was left to warm to room temperature and was stirred for 1 hour and 30 minutes was Added water (1.25 ml) and the mixture was left overnight to mix. The organic phase is separated by decantation, dried over Na2SO4and the solvent was removed under vacuum. The residue (276 mg) was dissolved in DCM and the solution was added Boc2O. the Mixture was left overnight to mixed, the solvent was removed under vacuum. The residue was purified by flash chromatography on silica gel, elwira a mixture of light petroleum ether and EtOAc (4:1, 2:1) with the formation of compound 25 (182 mg)as specified in the.

Synthesis 195

N-tert-Butoxycarbonyl-4-(4-aminophenoxy)-but-2-enylamine (26)

Nitrobenzophenone connection (25) (182 mg, 0.6 mmol) was dissolved in methanol (5 ml) and to the solution was added Na2S×9H2O (576 mg, 2.4 mmol) and the mixture had set to boil under reflux for 3 hours the Solvent was removed under vacuum, and the residue was distributed between water and Et2O (30 ml). The organic phase was extracted with 1 M aqueous HCl. The acidic aqueous extract was separated and podslushivaet 5 M aqueous NaOH to a pH of approximately 10. The mixture was extracted with Et2O (3×30 ml) and the combined organic phase was washed with saturated saline solution (30 ml). The extract was dried over Na2SO4, was filtered and was evaporated, obtaining the compound (26) (40 mg), specified in the header, in the form of a crude product.

Synthesis 196

{2-[4-(4-tert-Butoxycarbonylamino-but-2-ynyloxy)-phenyl]-1,1-dioxo-2,3-dihydro-1H-benzo[a]isothiazol-3-yl}-acetic acid (27)

Following the method similar to Method F (for the preparation of compounds 4), the connection specified in the header, was obtained from the chloride of sulfonyl (1.1) and aniline (26) in the form of a crude product.

Synthesis 197

2-{2-[4-(4-tert-Butoxycarbonylamino-but-2-ynyloxy)-phenyl]-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl}-N-hydroxyacetamido (28)

Following the method similar to Method N (for the preparation of compounds 5) of the carboxylic acid (27), the compound mentioned in the title, was obtained as the crude product.

Synthesis 198

Hydrochloric salt of 2-{2-[4-(4-Amino-but-2-ynyloxy)-phenyl]-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl}-N-hydroxyacetamido (29)

To a solution of compound (28) (40 mg, 0.09 mmol) in DCM (2.8 ml), protected N-BOC dropwise while cooling in an ice bath was added triperoxonane acid (1.4 ml). After complete addition, the ice bath was removed and the mixture was stirred at room temperature for 45 minutes, the Solvent and excess triperoxonane acid was removed under vacuum and the residue was treated with 2 M HCl in Et2O. the Mixture was evaporated, and the residue was re-treated with 2 M HCl in Et2O and again evaporated. The residue was treated with Et2O and the precipitate was collected on a filter, receiving the connection (29). Yield 68%, amorphous,1H-NMR (DMSO-d6, TMS) δ: 2.29-2.50 (2H, m, overlapping with DMSO); 3.79-3.83 (2H, m); 4.94 (2H, s); 5.46-5.53 (1H, m); 7.11 (2H, d, 8.1 Hz); 7.44 (2H, d, 8.1 Hz); 7.60-7.80 (3H, m); 7.95 (1H, d, 6.6 Hz); 8.40 (4H, s) and 10.59 ppm (1H, s).

Synthesis 199

Methyl ester (E)-3-(2-chlorosulfonyl-5-hydroxyphenyl)acrylic acid (31)

Following the method similar to Method A (for synthesis (1)) of the unsaturated complex ester (30), was the received specified in the title compound as crude product.

Synthesis 200

Methyl ester (5-hydroxy-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (32)

Solution of chloride of sulfonyl (31) (7,05 g, 25.5 mmol) and aniline (2.1) and 4.75 g, 51 mmol) in DCM (200 ml) was stirred for 17 h at room temperature. The solution is washed with 1 M aqueous HCl (200 ml) and saturated brine (3×100 ml) and dried over Na2SO4. The solution was filtered and evaporated with the formation of the intermediate product (8,13 g). It was dissolved in DMF (40 ml) was added K2CO3(6,74 g, for 48.9 mmol). The resulting mixture was heated at 80°C for 5 h, cooled to room temperature and poured into water (300 ml). The aqueous phase was extracted with EtOAc (2×250 ml). The combined organic phase was washed with saturated brine (3×100 ml), dried over Na2SO4, was filtered and was evaporated. The residue was purified by flash chromatography on silica gel, elwira a mixture of light petroleum ether-EtOAc (2:1, 1:1) with the formation of the product (32) (1.52 g).

Synthesis 201

Methyl ether (1,1-dioxo-2-phenyl-5-tripterocalyx-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (33)

To a solution of (32) (333 mg, 1 mmol) in DCM (5 ml) was added pyridine (0.16 ml, 2 mmol)and the solution was cooled in an ice bath. To a solution of portions anhydride was added to triptorelin honowai acid (0.2 ml, 1.2 mmol) and the resulting solution was left to warm to room temperature. Added 1M aqueous HCl (100 ml)and the mixture was extracted with EtOAc (2×150 ml). The combined organic phase was washed with saturated aqueous NaHCO3(100 ml) and saturated saline (100 ml) and dried over Na2SO4. The extract was filtered, and the solvent was removed under vacuum to education (33) (460 mg).

Synthesis 202

Methyl ether (1,1-dioxo-2,5-diphenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (34)

To a solution of compound (33) (460 mg, 1 mmol) in DME (10 ml) was added Pd(PhP)4(28 mg, 0.03 mmol), phenylboronic acid (133 mg, 1.1 mmol) and 2 M aqueous Na2CO3(1.3 ml, 2.6 mmol). The resulting mixture was heated at 85°C for 2 h and cooled to room temperature. It was dissolved in water (20 ml) and was extracted with EtOAc (2×20 ml). The combined organic phase was dried over Na2SO4, was filtered and was evaporated. The residue was purified by flash chromatography on silica gel, elwira a mixture of light petroleum ether and EtOAc (4:1) education (34) (340 mg).

Synthesis 203

(1,1-Dioxo-2,5-diphenyl-2,3-dihydro-1H-benzo[b]isothiazol-3-yl)acetic acid

Following the method similar to Method E (for synthesis (4)) of the complex ester (34), the connection specified in the header was received in widereaching product.

Synthesis 204

2-(1,1-Dioxo-2,5-diphenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)-N-hydroxyacetamido (36)

Following the method similar to Method G (for synthesis (5)) from carboxylic acid was obtained the connection specified in the header. Yield 80%, melting point: greater than 115°C. (dec.),1H-NMR spectrum (DMSO-d6, TMS) δ: 2.3-2.5 (1H, m, overlapping with DMSO); 2.69 (1H, dd, 3.7 Hz and 14.6 Hz); 5.75 (1H, dd, 4.4 Hz and 8.8 Hz); 7.34 (1H, m); 7.4-7.8 (N, m); 7.86 (1H, s); 7.9-8.2 (2H, m); 8.97 (1H, s), 10.55 ppm (1H, s).

Synthesis 205

Methyl ester (5-ethoxy-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (37)

A mixture of compound (32) (167 mg, 0.5 mmol), ethyl iodide (of 0.08 ml, 1.0 mmol) and K2CO3(415 mg, 1.5 mmol) in DMF (3 ml) was stirred at room temperature for 2 hours and 30 minutes the Mixture was diluted with water (20 ml) and was extracted with EtOAc (2×20 ml). The combined organic phase was washed with saturated saline (20 ml) and dried over Na2SO4. The extract was filtered and the solvent was removed under vacuum with the formation of compound (37) (180 mg)as specified in the header, in the form of a crude product.

Synthesis 206

(5 Ethoxy-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (38)

Following the procedure of Method F (for synthesis (4)) of the complex ester (37), the connection, indicated the data in the header, was obtained as the crude product.

Synthesis 207

2-(5-Ethoxy-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)-N-hydroxyacetamido (39)

Following the method similar to Method G (for synthesis (5)) of the carboxylic acid (38), was received on the connection specified in the header. Yield 35%, amorphous,1H-NMR (DMSO-d6, TMS): δ 1.36 (3H, t, 7 Hz); 2.31 (1H, dd, 8 Hz and 15 Hz); 2.60 (1H, dd, 4 Hz and 15 Hz); 4.13 (2H, q, 7 Hz); 5.60 (1H, dd, 7 Hz and 8 Hz); 7.0-7.4 (3H, m); 7.4-7.6 (4H, m); 7.86 (1H, d, 8 Hz), 8.94 (1H, s) and 10.51 ppm (1H, s).

Synthesis 208

Methyl ester (E)-3-(4-bromo-2-phenylsulfonyl)acrylic acid (40)

To a solution of aniline (2.1) (1.68 g, 18 mmol) in dioxane (20 ml) was added 1 M aqueous NaHCO3(15 ml). To the mixture was added a solution of chloride of sulfonyl (1.8) (3.3 g, 9.7 mmol) in dioxane (20 ml). The reaction mixture was stirred at room temperature for 1 h, diluted with 5% aqueous KHSO4(100 ml) and was extracted with EtOAc (100 ml). The organic phase was washed with saturated aqueous NaHCO3(100 ml) and saturated saline (100 ml). The extract was dried over Na2SO4was filtered and the solvent was removed under vacuum. The residue was treated with a mixture of hexane and EtOAc (2:1). The precipitate was collected on a filter, receiving (40) (1.8 g).

Synthesis 209

Methyl ester (E)-3-(3-Phenylsulfanyl-diphenyl-4-yl) acrylic sour is s (41)

A mixture of aryl bromide (40) (0.4 g, 1.0 mmol), phenylboronic acid (0,146 g, 1.2 mmol), Pd(Ph3P)4(35 mg, 0.03 mmol) and Cs2CO3(0,456 g, 1.4 mmol) were heated in dioxane (12 ml) at 90°C for 7 h, the Reaction mixture was cooled to room temperature and diluted with EtOAc (50 ml). The mixture is washed with 5% aqueous KHSO4(50 ml), saturated aqueous NaHCO3(50 ml) and saturated saline (50 ml). The organic phase was dried over Na2SO4, was filtered and was evaporated. The residue was treated with a mixture of hexane and EtOAc (3:1). The precipitate was collected on a filter, receiving (41) (0.21 g).

Synthesis 210

(1,1-Dioxo-2,6-diphenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (42)

A mixture of compound (41) (0.21 g, 0.54 mmol) in dioxane (4 ml) and 1 M aqueous NaHCO3(3 ml) was boiled under reflux for 8 hours was Cooled to room temperature and was diluted with water (40 ml). The product was extracted with EtOAc (50 ml) and the organic phase was washed with saturated saline (50 ml). The extract was dried over Na2SO4, was filtered and was evaporated, obtaining the compound (42) (0.18 g), specified in the header, in the form of a crude product.

Synthesis 211

2-(1,1-Dioxo-2,6-diphenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)-N-hydroxyacetamido (43)

Following the method similar to Method G (for the preparation of compounds (5)) of the carboxylic acid (42), received the connection specified in the header. Yield 45%, melting point: 191-193°C,1H-NMR (DMSO-d6, TMS): δ: 2.36 (1H, dd, 9.5 Hz, 14.7 Hz); 2.67 (1H, dd, 3.7 Hz, 14.7 Hz); 5.74 (1H, dd, 3.7 and 8.1 Hz); 7.3-7.6 (8H, m); 7.72 (1H, d, 8.1 Hz); 7.82 (2H, d, 6.6 Hz); 8.12 (1H, d, 8.1 Hz); 8.24 (1H, s); 8.96 (1H, s) and 10.56 ppm (1H, s).

General method of synthesis of 2-iodine-N-vinylbenzenesulfonic (45.1) and (45.2)

Method L: Solution sulfonamida (44) (3.7 mmol) in THF (20 ml) was cooled to 0°C in an argon atmosphere. Was added dropwise 1.4 M n-BuLi in hexano (5.7 ml, 7.9 mmol)and the mixture was left to warm to room temperature. After stirring at room temperature for 1 h and set the temperature of the reaction mixture -78°C. and to the solution was added l2(1.04 g, 4,11 mmol) in THF (12 ml). The mixture was stirred at -78°C for 1 h, and then left to warm to room temperature. Added concentrated aqueous Na2S2O3until the colour disappears, and the mixture was extracted with EtOAc (3×50 ml). The combined organic phase was washed with saturated saline (100 ml) and dried over Na2SO4. After evaporation of the solvent formed crude product (45).

Following the method similar to Method L, were in the form of products obtained the following compounds.

SynthesisMethod NameStructure
212L2-Iodine-4-methyl-N-vinylbenzenesulfonic (45.1)
213L4-Chloro-2-Iodine-N-vinylbenzenesulfonic (45.2)

General methods of synthesis of the methyl esters of 2-(1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (46.1) and (46.2)

Method M: a Mixture of 2-iodine-N-vinylbenzenesulfonic (45) (1.3 mmol), Pd(OAc)2(28 mg, 0.13 mmol), tri-orthotolidine (77,3 mg, 0.25 mmol), triethylamine (1 ml, 7.2 mmol) and methyl acrylate (2.37 ml, and 25.4 mmol) in DMF (3 ml) was heated at 110°C for 3 hours After cooling to room temperature was added water (50 ml)and the mixture was extracted with EtOAc (3×30 ml). The combined organic phase was dried over Na2SO4, was filtered and was evaporated. The residue was purified by flash chromatography on silica gel, elwira a mixture of light petroleum ether and EtOAc (5:1) with the formation (46).

Following the method similar to method M, were obtained the following compounds in the form of a crude product.

Synthesis MethodNameStructure
214MMethyl ester of 2-(5-methyl-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (46.1)

SynthesisMethodNameStructure
215MMethyl ester of 2-(5-chloro-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (46.2)

Synthesis 216

2-(5-Methyl-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (47.1)

Following the method similar to Method E (for synthesis (4)) of the complex ester (46.1), the connection specified in the header was received in the form of a crude product.

Synthesis 217

2-(5-Chloro-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl) acetic acid (47.2)

Following the method similar to Method E (for synthesis (4)) of the complex ester (46.2), the connection specified in the header, it was Paul who was identified as the crude product.

Synthesis 218

2-(5-Methyl-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)-N-hydroxyacetamido (48.1)

Following the method similar to Method G (for synthesis (5)) of the carboxylic acid (47.1)were received for the connection specified in the header. Yield 45%, melting point: 150-155°C,1H-NMR (DMSO-d6, TMS) δ: 2.30 (dd, J=14.7 and 9.0 Hz, 1H); 2.46 (s, overlapping with DMSO, 3H); 2.62 (dd, J=14.7 3.8 Hz, 1H, overlap with DMSO); 5.57-5.70 (m, 1H); 7.26-7.38 (m, 1H); 7.40-7.57 (m, 6N); 7.86 (d, J=7.9 Hz, 1H); 8.95 (s, 1H); 10.52 ppm (s, 1H).

Synthesis 219

(5-Chloro-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)-N-hydroxyacetamido (48.2)

Following the method similar to Method N (for the synthesis of (5)) of the carboxylic acid (47.1)were received for the connection specified in the header. Yield 80%, melting point: 192-194°C,1H-NMR (DMSO-d6, TMS) δ: 2.41 (dd, J=15.0 and 8.3 Hz, 1H); 2.70 (dd, J=15.0 and 4.0 Hz, 1H); 5.70 (dd, J=8.0 and 4.0 Hz, 1H); 7.30-7.41 (m, 1H); 7.44-7.52 (m, 4H); 7.73-7.82 (m, 2H); 8.05 (d, J=8.9 Hz, 1H); 8.94 (s, 1H) and 10.49 ppm (s, 1H).

General method of preparation of N-vinylbenzenesulfonic (50.1)-(50.11)

Method N: Aniline (2.1) (0,70 g, 7.5 mmol) suspended in 1 M aqueous NaHCO3(15 ml). To the suspension was added a solution of chloride of sulfonyl (49) (5 mmol) in dioxane (15 ml)and the mixture was stirred at room temperature for 22 hours It was diluted with 5% aqueous KHSO4(40 ml). The precipitate was collected n is the filter and washed with plenty of water. The material was thoroughly dried under vacuum over P2O5with the formation (50).

Following the method similar to Method N, were obtained the following compounds in the form of a crude product.

SynthesisMethodNameStructure
220N3-Methoxy-N-vinylbenzenesulfonic (50.1)
221N3-Chloro-N-vinylbenzenesulfonic (50.2)
222N2-Trifluoromethyl-N-vinylbenzenesulfonic (50.3)
223N2-Fluoro-4-methyl-N-vinylbenzenesulfonic (50.4)
224N3-Chloro-4-fluoro-N-vinylbenzenesulfonic (50.5)

SynthesisMethodNameStructure225N4-Fluoro-N-vinylbenzenesulfonic (50.6)226N2-Chloro-N-vinylbenzenesulfonic (50.7)227N3,5-Dichloro-N-vinylbenzenesulfonic (50.8)228N3-Trifluoromethyl-N-vinylbenzenesulfonic (50.9)229N5-Bromo-2-methoxy-N-vinylbenzenesulfonic (50.10)230N4-Chloro-2-fluoro-N-vinylbenzenesulfonic (50.11)

General method of preparation of 1,1-dioxo-2-phenyl-2,3-digitron-benzo[d]isothiazol-3-ol (51.1)-(51.11)

Method A: a Solution sulfonamida (50) (2.5 mmol) in THF (25 ml) was cooled to 0°C for the synthesis of compounds 51.1, 51.3, or to -78°C for synthesis of compounds 51.2, 51.4-51.11). Was added dropwise 1.6 M n-BuLi in hexano (3.5 ml, 5.5 mmol) and the mixture was stirred under cooling for 2 hours could Set the temperature of the mixture -78°C and one portion was added DMF (of 0.39 ml, 5.0 mmol). Was sacked cooling bath, and the mixture was left to warm up to reach room temperature and was stirred for 2 hours was Added 5% aqueous KHSO4(100 ml)and the mixture was extracted with EtOAc (200 ml). The organic phase was separated and washed with saturated saline (100 ml). The extract was dried over Na2SO4, was filtered and was evaporated. The residue was purified by flash chromatography on silica gel, elwira a mixture of light petroleum ether and EtOAc.

Following a methodology similar Way, the following compounds were obtained in the form of the crude product.

SynthesisMethodNameStructure
231About4-Methoxy-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-ol (51.1)
232About4-Chloro-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-ol (51.2)
233About7-Trifluoromethyl-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-ol (51.3)

SynthesisMethodNameStructure
234About7-Fluoro-5-methyl-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-ol (51.4)
235About4-Chloro-5-fluoro-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-ol (51.5)
236About5-fluoro-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-ol (51.6)
237About7-Chloro-1,1-dioxo-2-f the Nile-2,3-dihydro-1H-benzo[d]isothiazol-3-ol (51.7)
238About4,6-Dichloro-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-ol (51.8)
239About6-Trifluoromethyl-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-ol (51.9)

SynthesisMethodNameStructure
240About7-Methoxy-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-ol (51.10)
241About5-Chloro-7-fluoro-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-ol (51.11)

General method of preparation of methyl esters of 2-(1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (52.1)-(52.12)

Method D: To a solution of compound (51) (215 mg, 0.75 mmol) and trimethylphosphate (0.16 ml, 1 mmol) was added 1 M NaOMe in Meon (1.5 ml, 1.5 mmol). The mixture was left overnight to mix at room temperature and was diluted with water (50 ml). Usually formed white precipitate, which was collected on a filter, washed on the filter with water and dried under vacuum over P2O5with the formation 52. If the filtered precipitate was not formed, the product was extracted with EtOAc, and the organic phase was washed with saturated saline solution. Drying over Na2SO4, filtration and removal of solvent gave the residue, which was purified flash chromatography on silica gel, elwira a mixture of light petroleum ether and EtOAc with the formation 52.

Following the method similar to Method P, the following compounds were obtained in the form of the crude product.

SynthesisMethodNameStructure
242PMethyl ester of 2-(4-methoxy-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (52.1)

SynthesisMethodName Structure
243PMethyl ester of 2-(4-chloro-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (52.2)
244PMethyl ester of 2-(7-trifluoromethyl-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (52.3)
245PMethyl ester of 2-(7-fluoro-5-methyl-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (52.4)
246PMethyl ester of 2-(4-chloro-5-fluoro-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (52.5)
247PMethyl ester of 2-(5-fluoro -1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (52.6)
248Pmilovy ester 2-(7-chloro-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (52.7)

SynthesisMethodNameStructure
249PMethyl ester of 2-(4,6-dichloro-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (52.8)
250PMethyl ester of 2-(6-trifluoromethyl-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (52.9)
251PMethyl ester of 2-(7-methoxy-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (52.10)
252PMethyl ester of 2-(5-chloro-7-methoxy-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (52.11)
253P Methyl ester of 2-(4-chloro-5-methoxy-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (52.12)

Following the method similar to Method E (for synthesis (4)), and applying the above esters, the following compounds were obtained as crude products.

SynthesisHow + ReagentNameStructure
254E+(52.1)2-(4-Methoxy-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (53.1)
255E+(52.2)2-(4-Chloro-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (53.2)
256E+(52.3)2-(7-Trifluoromethyl-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (53.3)
257E+(52.4) 2-(7-Fluoro-5-methyl-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (53.4)
258E+(52.5)2-(4-Chloro-5-fluoro-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (53.5)
259E+(52.6)2-(5-fluoro-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (53.6)

SynthesisHow + ReagentNameStructure
260E+(52.7)2-(7-Chloro-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (53.7)
261E+(52.8)2-(4,6-Dichloro-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (53.8)
262 E+(52.9)2-(6-Trifluoromethyl-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (53.9)
263E+(52.10)2-(7-Methoxy-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (53.10)
264E+(52.11)2-(5-Chloro-7-Methoxy-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (53.11)
265E+(52.13)(4-Chloro-5-Methoxy-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)acetic acid (53.12)

Following the method similar to Method N (for the synthesis of (5)), and applying the above-mentioned carboxylic acid, there were obtained the following compounds in the form of a crude product.

SynthesisHow + ReagentNameStructure
266 H+(53.1)2-(4-Methoxy-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl))-N-hydroxyacetamido (54.1)
267H+(53.2)2-(4-Chloro-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)-N-hydroxyacetamido (54.2)
268H+(53.3)2-(7-Trifluoromethyl-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl))-N-hydroxyacetamido (54.3)
269H+(53.4)2-(7-Fluoro-5-methyl-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)-N-hydroxyacetamido (54.4)
270H+(53.5)2-(4-Chloro-5-fluoro-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)-N-hydroxyacetamido (54.5)

SynthesisHow + ReagentNameThe structure is and
271H+(53.6)2-(5-fluoro-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)-N-hydroxyacetamido (54.6)
272H+(53.7)2-(7-Chloro-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)-N-hydroxyacetamido (54.7)
273H+(53.8)2-(4,6-Dichloro-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)-N-hydroxyacetamido (54.8)
274H+(53.9)2-(6-Trifluoromethyl-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)-N-hydroxyacetamido (54.9)
275H+(53.10)(7-Methoxy-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)- N-hydroxyacetamido (54.10)
276H+(53.11)(5-Chloro-7-methoxy-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-yl)-N-hydroxyacetamido (54.11)

SynthesisHow + ReagentNameStructure
277H+(53.12)(4-Chloro-5-Methoxy-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)-N-hydroxyacetamido (54.12)

The compound (54.1): Yield 64%, melting point 188-190°C,1H-NMR (DMSO-d6, TMS) δ: 2.4-2.6 (2H, overlapping with DMSO); 3.90 (3H, s); 5.66 (1H, t, 5.0 Hz); 7.23-7.46 (7H, CH); 7.66 (1H, 18.0 Hz); 8.66 (1H, s) and 10.29 ppm (1H, s).

The compound (54.2): Yield 54%, melting point 204-206°C,1H-NMR (DMSO-d6, TMS) δ: 2.63 (1H, dd, 15.4 Hz, 4.4 Hz); 2.75 (1H, dd, 15.4 Hz, 5.9 Hz); 5.81 (1H, t, 4.4 Hz); 7.27-7.51 (5H, m); 7.71 (1H, t, 7.7 Hz); 7.88 (1H, d, 7.3 Hz); 7.95 (1H, d, 7.3 Hz); 8.70 (1H, s), 10.37 ppm (1H, s).

Connection (54.3): Yield 48%, melting point 187-189°C,1H-NMR (DMSO-d6, TMS) δ: 2.3-2.5 (1H, m, overlapping with DMSO); 2.70 (1H, dd, 4.4 and 14.7 Hz); 5.74 (1H, dd, 4.4 Hz and 8.1 Hz); 7.33-7.56 (5H, m); 7.95-8.14 (3H, m); 8.90 (1H, s) and 10.47 ppm (1H, s).

Connection (54.4): Yield 37%, amorphous powder,1H-NMR (DMSO-d6, TMS) δ: 2.34 (1H, dd, 8.1, and 14.7 Hz, partial overlap with DMSO); 2.45 (3H, s, overlapping with DMSO); 2.61 (1H, dd, 4.4 and 8.1 Hz, partial overlap with DMSO); 5.6 (1H, dd, 3.7 Hz and 8.8 Hz); 7.2-7.6 (7H, m); 8.90 (1H, s) and 10.46 ppm (1H, s). MS (mass spectroscopy): 350.9 (M+).

Connection (54.5): Yield 50%, amorphous powder,1H-NMR (DMSO-d6, TMS) δ: 2.6-2.9 (2H, m, partially overlapping with DMSO); 5.82 (1H, t, 4.4 Hz); 7.2-7.5 (5H, m); 7.7-7.9 (1H, m); 8.0-8.2 (1H, m); 8.71 (1H, d, 1.5 Hz) and 10.37 ppm (1H, d, 1.5 Hz). MS: 370.9 (M+).

Connection (54.6): Yield 80%, amorphous powder,1H-NMR (DMSO-d6, TMS) δ: 2.3-2.8 (2H, m, partially overlapping with DMSO); 5.64 (1H, dd, 3.7 Hz and 8.1 Hz); 7.2-7.4 (1H, m); 7.4-7.7 (7H, m); 8.08 (1H, dd, 5.1 Hz and 8.8 Hz); 8.90 (1H, s) and 10.47 ppm (1H, s). MS: 337.0 (M+).

Connection (54.7): Yield 99%, melting point: more than 188°C. (dec.),1H-NMR (DMSO-d6, TMS) δ: 2.33 (1H, dd, 8.1 Hz, 14.7 Hz); 2.64 (1H, dd, 3.7 Hz, of 14.7 Hz); 5.67 (1H, dd, 4.4 Hz and 8.1 Hz); 7.3-7.9 (8H, CH); 8.88 (1H, s) and 10.46 ppm (1H, s). MS: 352.9 (M+).

Connection (54.8): Yield 60%, melting point: more than 150°C (dec.),1H-NMR (DMSO-d6, TMS) δ: 2.4-2.7 (1H, m, partially overlapping with DMSO); 2.79 (1H, dd, 16.1 Hz and 5.1 Hz); 5.77 (1H, t, 4.4 Hz); 7.2-7.4 (1H, m); 7.46 (4H, m); 8.08 (1H, d, 2.0 Hz); 8.23 (1H, d, 2.0 Hz); 8.69 (1H, s) and 10.36 ppm (1H, s). MS: 386.8 (M+).

Connection (54.9): Yield 60%, amorphous powder1H-NMR (DMSO-d6, TMS) δ: 2.3-2.8 (2H, m, overlapping with DMSO); 5.79 (1H, dd, 3.9 Hz and 7.8 Hz); 7.3-7.6 (5H, m); 7.88 (1H, d, 7.8 Hz); 8.19 (1H, d, 7.8 Hz); 8.52 (1H, s); 8.89 (1H, s), 10.45 ppm (1H, s). MS: 387.0 (M+).

Connection (54.10): Yield 40%, melting point: more than 161°C (dec.),1H-NMR (DMSO-d6, TMS) δ: 2.2-2.7 (2H, m, overlapping with DMSO); 3.95 (3H, s); 5.59 (1H, dd, 2.9 Hz and 8.8 Hz); 7.10 (1H, d, 6.7 Hz); 7.-7.6 (8H, m); 7.72 (1H, t, 8.8 Hz); 8.90 (1H, s), and 10.49 ppm (1H, s). MS: 348.9 (M+).

Connection (54.11): Yield 65%, the melting point greater than 170°C (dec.)1H-NMR (DMSO-d6, TMS) δ: 2.2-2.7 (2H, m, partially overlapping with DMSO); 3.98 (3H, s); 5.59 (1H, dd, 3.7 Hz and 8.1 Hz); 7.2-7.6 (7H, m); 8.90 (1H, d, 1.5 Hz) and 10.46 ppm (1H, d, 1.5 Hz). MS: 382.8 (M+).

Connection (54.12): Yield 42%, melting point 184-188°C (dec.),1H-NMR (DMSO-d6, TMS) δ: 2.5-2.7 (2H, m, partially overlapping with DMSO); 3.99 (3H, s); 5.74 (1H, t, 4.4 Hz), 7.2-7.6 (6N, m); 7.7-7.9 (1H, m); 7.94 (1H, d, 8.1 Hz); 8.68 (1H, s), 10.37 ppm (1H, s). MS (mass spectrum): 382.9 (M+).

Synthesis 278

3-(1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)propionitrile (55)

A solution of ester (3.1) (2.9 g, 9,14 mmol) in THF (70 ml) was cooled in an ice bath and to it several portions was added LiAlH4(1.04 g, a 27.4 mmol). The mixture was left to warm to room temperature and was further stirred 1 h Residual LiAlH4destroyed by adding water dropwise until gel formation. Was added a saturated solution of potassium-sodium salt of tartaric acid (100 ml)and the resulting suspension was extracted with EtOAc (300 ml). The organic phase was washed with saturated saline (100 ml) and dried over Na2SO4. The solution was filtered and evaporated with the formation of the intermediate alcohol. The obtained intermediate product (1,16 g) was dissolved in DCM (70 ml) and to the solution was added PCl5(0,92g, 4.4 mmol). The mixture was stirred at room temperature for 1 h, washed with saturated aqueous NaHCO3(100 ml). The organic phase was evaporated, and the residue was purified flash chromatography on silica gel, elwira a mixture of light petroleum ether and EtOAc (1:1), obtaining the intermediate chloride (610 mg). It was dissolved in DMF (15 ml) was added KCN (258 mg, of 3.96 mmol). The mixture was stirred at 50°C for 20 h and was diluted with water (100 ml). The product was treated with EtOAc (100 ml)and the organic phase was washed with saturated saline (100 ml). The solution was dried over Na2SO4, was filtered and was evaporated. The residue was purified by flash chromatography on silica gel, elwira a mixture of light petroleum ether and EtOAc (1:1), receiving the connection specified in the header (55) (450 mg).

Synthesis 279

3-(1,1-Dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)propionic acid (56)

To a solution of nitrile (55) (136 mg, 0.46 mmol) in dioxane (7 ml) was added aqueous concentrated HCl (1.2 ml, 14.4 mmol). The mixture was heated at 115°C for 72 h and was evaporated. The residue was purified by flash chromatography on silica gel, elwira a mixture of light petroleum ether and EtOAc (1:10)to give compound (56) (138 mg).

Synthesis 280

3-(1,1-Dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)-N-hydroxypropionate (57)

Following m is todica, similar to Method G (for synthesis (5)) of the carboxylic acid (56) received the connection specified in the header. Yield 63%, viscous oil,1H-NMR (DMSO-d6, TMS) δ: 1.38-1.58 (m, 1H); 1.76-1.96 (m, 1H); 2.03-2.35 (m, 2H); 5.68 (t, J=3.1 Hz, 1H); 7.28-7.41 (m, 1H); 7.45-7.57 (m, 4H); 7.65-7.90 (m, 3H); 7.98 (d, J=7.7 Hz, 1H); at 8.62 (s, 1H); 10.29 ppm (s, 1H).

Synthesis 281

2-Methyl-N-vinylbenzenesulfonic (59.1)

Following the method similar to Method N (for the synthesis of compounds (50))from chloride sulfonyl (58.1) and aniline (2.1) was obtained the connection specified in the header, in the form of a crude product.

Synthesis 282

2-Methyl-3-chloro-N-vinylbenzenesulfonic (59.2)

Following the method similar to Method N (for the synthesis of compounds (50))from chloride sulfonyl (58.2) and aniline (2.1) was obtained the connection specified in the header, in the form of a crude product.

tert-butyl ether 1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-carboxylic acid (60.1) and (60.2)

Method Q: Solution sulfonamida (58) (2.8 mmol), BOC2O (1.2 g, 5,54 mmol) and DMAP (338 mg, 2.8 mmol) in THF (35 ml) was left for the night mixed at room temperature. The solvent was removed under vacuum, and the residue was treated with EtOAc (100 ml). The organic phase is washed with 10% aqueous HCl, saturated aqueous NaHCO3and saturated salt solution. The extract was dried over Na2 SO4, was filtered and was evaporated. The residue was purified by flash chromatography on silica gel, elwira a mixture of light petroleum ether and EtOAc (4:1). The intermediate compound (2.0 mmol) was dissolved in THF and to it was added TMEDA (0,66 ml, 4.4 mmol)and the mixture was cooled to -78°C. At this temperature, was added dropwise 1.5 M t-BuLi in hexano (2,9 ml, 4.4 mmol)and the mixture was stirred at -78°C. an additional 30 minutes Added chloride anhydride dimethylaminoethanol acid (to 0.24 ml, 2.2 mmol), the mixture was stirred at

-78°C for 1 h, it was allowed to warm up to reach room temperature and then at night, mixed. The mixture was diluted with EtOAc and washed with saturated saline solution. The organic phase was dried over Na2SO4, was filtered and was evaporated. The residue was purified by flash chromatography on silica gel, elwira a mixture of light petroleum ether and EtOAc (4:1)to give compound (60)specified in the header.

Following the method similar to Method Q, were obtained the following compounds in the form of a crude product.

SynthesisMethodNameStructure
283Qtert-Butilovyi 1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-carboxylic acid (60.1)
284Qtert-Butyl ether 4-chloro-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-carboxylic acid (60.2)

Following the method similar to Method E (for synthesis (4)), and applying the above ester, the following compound was obtained in the form of a crude product.

SynthesisHow + ReagentNameStructure
285E+(60.1)1,1-Dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-carboxylic acid (61.1)
286E+(60.2)4-Chloro-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-carboxylic acid (61.2)

Following the method similar to Method G (for synthesis (5)), and applying the above carboxylic acid were obtained compound as crude product.

SynthesisHow + ReagentNameStructure
287G+(61.1)Hydroxylated 1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[a]isothiazol-3-carboxylic acid (62.1)
288G+(61.2)Hydroxylated 4-chloro-1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-carboxylic acid (62.2)

Connection (62.1): Yield 95%, melting point 188-191°C,1H-NMR (DMSO-d6, TMS) δ: 5.78 (s, 1H); 7.22-7.32 (m, 1H); 7.41-7.51 (m, 4H); 7.62-7.91 (m, 3H); 8.00-8.08 (m, 1H); 9.34 (s, 1H); 11.35 ppm (s, 1H).

Connection (62.2): Yield 43%, melting point 167-170°C,1H-NMR (DMSO-d6, TMS) δ: 5.72 (s, 1H); 7.30-7.43 (m, 1H); 7.46-7.55 (m, 4H); 7.78 (dd, J=8.0 and 8.0 Hz, 1H); 7.91 (dd, J=0.9 and 8.0 Hz, 1H); 8.05 (dd, J=0.9 and 8.0 Hz, 1H); 9.35 (d, J=1.0 Hz, 1H); 11.31 ppm (s, 1H).

Synthesis 289

(+)- and (-)-1,1-Dioxo-2-phenyl-2,3-dihydro-1H-benzo[d]isothiazol-3-yl)-N-hydroxyl-acetamide (+)-(S)-(5.1) and (-)-(R) (5.1)

A solution of carboxylic acid (4.1) (606 mg, 2 mmol), (R)-phenylglycinol (274 mg, 2 mmol), HOBt (270 mg, 2 mmol) and EDCl (383 mg, 2 mmol) in DMF (2 ml) was left at night per mesyatsa at room temperature. The solution was distributed between EtOAc (30 ml) and water (30 ml). The organic phase was separated and washed with saturated saline (20 ml), saturated aqueous NaHCO3(20 ml) and saturated saline (20 ml). The solution was dried over Na2SO4, was filtered and was evaporated. Diastereomeric amides were separated by chromatography using a rotating electrode on silica gel, elwira a mixture of hexane-ethyl acetate (1:2), with the formation quickly eluruumideta of diastereoisomer (S,R)-(63.1) (structure determined by x-ray spectroscopy) and slowly eluruumideta of diastereoisomer (R,R)-(63.1).

Each of the diastereomeric amides (S,R)-(63.1) and (R,R)-(63.1) was obtained in 20% aqueous HCl at 80°C for 7 hours. The product was extracted with CHCl3and the solution was dried over Na2SO4. The solution was filtered and evaporated with the formation of carboxylic acid (S)-(4.1) and (R)-(4.1). Carboxylic acid (S)-(4.1) and (R)-(4.1) was transferred into the hydroxamic acid, (+)- (S)-(5.1) ([α]D20=+80° (C=1, acetone)and (-)-(R)-(5.1) ([α]D20=-92° (C=1, acetone)), following the General procedure described for the synthesis of racemic hydroxamic acid (5.1) and had data1H-NMR, is identical to the data for racemic hydroxamic acid (5.1).

Synthesis 290

(+)- and (-)-2-[2-(4-But-2-injectively)-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl]-N-hydroxyacetamido (+)-(5.43) and (-)-(5.43)

A solution of carboxylic acid (4.43) (1,11 g, 3.0 mmol), (R)-phenylglycinol (0.45 g, 3.3 mmol), HOBt (0.45 g, 3.3 mmol) and EDCl (to 0.63 g, 3.3 mmol) in DMF (15 ml) was stirred at room temperature for 24 h the Solution was distributed between EtOAc (70 ml) and water (100 ml). The organic phase was separated and washed with water (2×100 ml), and saturated salt solution (100 ml), the solution was dried over Na2SO4, was filtered and was evaporated. Diastereomeric amides were separated by flash chromatography on silica gel, elwira EtOAc education quickly eluruumideta diastereomeric amide E7-(63.2) (0,67 g) and E2(63.2) (0.56 g) slowly eluruumideta diastereomeric amide. Each of the diastereomeric amides E1-(63.2) (343 mg) and E2(63.2) (343 mg) was hydrolyzed in a mixture of 1 M aqueous H2SO4(12 ml) and dioxane (12 ml) at the boiling temperature under reflux for 30 hours, the Dioxane was removed under vacuum and added water (30 ml). The mixture was extracted with EtOAc (50 ml + 30 ml)and the combined organic phase was washed with saturated saline (50 ml), the solution was dried over Na2SO4, was filtered and was evaporated with the formation of carboxylic acids E1-(4.43) (242 mg) and E2-(4.43) (269 mg), respectively. Carboxylic acid E7-(4.43) and E2-(4.43) was transferred into the hydroxamic acid, (+)- (5.43) ([α]D20=+71° (C=0,86, acetone)and (-)-(5.43) ([α]D20=-69° (C=0,84, acetone)), following the General procedure described for the synthetic is and racemic hydroxamic acid (5.43), and had data1H-NMR, is identical to the data for racemic hydroxamic acid (5.43).

Synthesis 291

(+)- and (-)-2-{2-[4-(2-Methylinosine-4-ylethoxy)phenyl]-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-3-yl}-N-hydroxyacetamido (+)-(5.44) and (-)-(5.44)

A solution of carboxylic acid (4.44) (1,02 g, 2.0 mmol), (R)-phenylglycinol (0.27 g, 2.0 mmol), HOBt (0.27 g, 2.0 mmol) and EDCl (or 0.38 g, 2.0 mmol) in DMF (4 ml) was stirred at room temperature for 15 hours, the Mixture was diluted with saturated aqueous NaHCO3(100 ml) and was extracted with EtOAc (2×100 ml). The combined organic phase was separated and washed with saturated saline (100 ml). The solution was dried over Na2SO4, was filtered and was evaporated. Diastereomeric amides shared flash chromatography on silica gel, elwira EtOAc education quickly eluruumideta diastereomeric amide E7-(63.3) (0,30 g) and slow Alyonushka diastereomeric amide E2-(63.3) (0.27 g). Each of the diastereomeric amides E7-(63.3) (140 mg) and E2-(63.3) (150 mg) was hydrolyzed in a mixture of 10% aqueous HCl (0,92 ml) and dioxane (0,92 ml) at 110°C for 2 hours, the Dioxane was removed under vacuum and added water (4 ml). The precipitate was separated by centrifugation and repeatedly washed with water. The residue was dried over P2O5under vacuum with the formation of carboxylic acids E1-(4.44) (0.11 g) and E2-(4.44) (0.10 g), respectively. To benovoy acid E1(4.44) (102 mg, 0.2 mmol) was dissolved in dioxane (2 ml) and to it was added chloride anhydride, oxalic acid (0.35 ml, 4 mmol) and then a drop of DMF. The mixture was heated at 50°C for 2 h and evaporated. To the residue was added a solution of O-TNR hydroxylamine (117 mg, 1 mmol) in DMF (1 ml)and the resulting mixture was stirred at room temperature for 30 minutes the Mixture was diluted with saturated aqueous NaHCO3(10 ml) and was extracted with EtOAc (15 ml). The extract was dried over Na2SO4, was filtered and was evaporated. The residue was purified by flash chromatography on silica gel, elwira EtOAc with the formation of a secure On-TNR hydroxamic acid (64 mg). The intermediate compound was dissolved in dioxane (1.2 ml) and to the solution was added 1 M aqueous HCl (0.6 ml). The mixture was left overnight to mix at room temperature and neutralized aqueous 1 M NaHCO3(10 ml). The precipitate was collected on a filter and washed several times with water. The residue was dried over P2O5under vacuum and was treated with MeCN (2 ml). The precipitate was collected on a filter and dried over P2O5under vacuum with the formation of hydroxamic acid (+)-5.44 ([α]D20=+62° (C=0.5, DMSO-d6))having a range of1H-NMR identical to the spectrum of racemic hydroxamic acid (5.44).

Following the above procedure, the carboxylic acid E2-(4.44) (180 mg, 0.35 mmol) were transferred into hydroxamate the acid (-)-5.44 ([α] D20=-48° (C=0.5, DMSO-d6))having a range of1H-NMR identical to the spectrum of racemic hydroxamic acid (5.44).

Synthesis 292

O-(N,N-Diethylthiocarbamoyl)-2-hydroxybenzaldehyde (65)

N,N-Dimethylthiocarbamate (7,42 g, 60 mmol) was added to a solution of salicylic aldehyde (64 (4,89 g, 40 mmol) and DABCO, 1,4-diazabicyclo[2.2.2]octane, (8,96 g, 80 mmol) in DMF (80 ml). The resulting mixture was left overnight to mix at room temperature and poured into water (250 ml). The precipitate was collected on a filter and washed with plenty of water. After drying over NaOH under vacuum connection (65) (7,34 g, 87%) was obtained as a pale gray crystals.1H-NMR (DMSO-d6) δ: 3.38 and 3.40 (just 6N, both s); 7.24 (1H, d, 8 Hz); 7.46 (1H, t, 7 Hz); 7.74 (1H, dt, 7 Hz and 2 Hz); 7.86 (1H, dd, 8 Hz and 2 Hz) and 10.00 ppm (1H, s).

Synthesis 293

8-(N,N-Diethylthiocarbamoyl)-2-thiobenzamide (66)

The compound (65) (1.04 g, 5 mmol) was heated in N,N-diethylaniline (1 ml) at 190°C for 5 hours, After cooling, was added water (10 ml)and the mixture was acidified with 20% aqueous KHSO4. The product was treated with ethyl acetate (20 ml). The organic phase was separated and washed with saturated saline (20 ml). After drying over Na2SO4the solvent was removed under vacuum, and the residue was purified flash chromatography on silica gel, elwira a mixture of the light is malanova ether and ethyl acetate (2:1) with the formation of compound (66) (495 mg, 48%).1H-NMR (DMSO-d6, TMS) δ: 2.91 (3H, br s), 3.09 (3H, br s); 7.5-7.8 (3H, m); 7.8-8.0 (2H, m); and 10.14 ppm (1H, s).

Synthesis 294

8-Benzyl-2-thiobenzamide (67)

Connection (66) (495 mg, 2.4 mmol) was dissolved in a solution of 1M methanolic NaOMe (10 ml). The mixture was left overnight to mix at room temperature and to it was added benzyl bromide (0.35 ml, 2.9 mmol). stirring was continued for 2 h, and the mixture was poured into ice water (50 ml). The product was treated with CH2Cl2(3×20 ml). The combined organic phase was washed with saturated saline and dried over Na2SO4. The solution was filtered and was evaporated with obrazovanii of dimethylacetal aldehyde. It was dissolved in a mixture of dioxane (2 ml) and 1 N. aqueous HCl (1 ml) and was stirred for 2 hours and 30 minutes at room temperature, was added water (20 ml)and the mixture was extracted with EtOAc (30 ml). The organic phase was separated, washed with saturated saline (20 ml) and dried over Na2SO4. The solution was filtered and evaporated to education (67) (417 mg, 76%) as oil.1H-NMR (DMSO-d6, TMS) δ: 4.26 (2H, s); 7.2-7.5 (6N, m); 7.6-7.7 (2H, m); 7.87 (1H, d, 8 Hz) and 10.10 ppm (1H, s).

Synthesis 295

Methyl ester (E)-3-(2-Benzylaniline)acrylic acid (68)

A solution of aldehyde (67) (1.24 g, 5.5 mmol) and methyl(triphenylphosphonium)acetate (1,93 g ,8 mmol) in CH 2Cl2(30 ml) was stirred at room temperature for 2 hours. Was added silica gel (3 small portions), and the solvent was evaporated. The residue was poured on short silicagel column, and the product was suirable with a mixture of hexane and EtOAc (10:1) with the formation of ester (68) in the form of colorless crystals (985 mg, 63%).1H-NMR (CDCl3, TMS) δ: 3.81 (3H, s); 4.03 (2H, s); 6.32 (1H, d, 15 Hz); 7.2-7.7 (N, m) and 8.20 ppm (1H, d, 15 Hz).

Synthesis 296

Methyl ester (E)-3-(2-phenylmethanesulfonyl)acrylic acid (69)

To a solution of compound (68) (853 mg, 3 mmol) in CH2Cl2(30 ml) was added 70% MSRWA, metallocarboxypeptidase acid (1.84 g, 7.5 mmol). The mixture was stirred at room temperature for 1 hour and was additionally added CH2Cl2(30 ml). The organic phase was washed with saturated aqueous Na2S2O3(20 ml) and saturated aqueous NaHCO3. The solution was dried over Na2SO4and was evaporated. The residue was led from a mixture of hexane and EtOAc (4:1) with the formation of compound (69) (613 mg, 65%) as colorless crystals.1H-NMR (DMSO-d6, TMS) δ: 3.73 (3H, s); 4.61 (2H, s); 6.46 (1H, d, 16 Hz); 7.0-8.0 (N, m) and 8.17 ppm (1H, d, 16 Hz).

Synthesis 297

Methyl ester 2-(1,1-dioxo-2-phenyl-2,3-dihydro-1H-benzo [b]thiophene-3-yl)acetic acid (70)

1 M aqueous NaHCO3(0,64 ml) to relax is to the solution of compound (69) (0.32 mmol, 100 mg) in dioxane (1.2 ml). The mixture was boiled under reflux for 45 minutes and evaporated. The residue was distributed between EtOAc (20 ml) and water (20 ml). The organic phase was separated and washed with saturated saline (20 ml). The solution was dried over Na2SO4filtered and evaporated. The residue was treated with hexane and filtered with the formation of compound (70) (78 mg, 78%) as colorless crystals.1H-NMR (DMSO-d6, TMS) δ: 2.84 (1H, dd, 16 Hz and 6 Hz); 3.02 (1H, dd, 16 Hz and 6 Hz); 3.40 (3H, s); 4.15 (1H, m); 4.88 (1H, d, 9 Hz); 7.45 (5H, s), 7.5-7.8 ppm (4H, m).

Synthesis 298

2-(1,1-Dioxo-2-phenyl-2,3-dihydro-1H-benzo[b]thiophene-3-yl)acetic acid (71)

A solution of ester (70) (175 mg, 0.55 mmol) in a mixture of dioxane (3.3 ml) and concentrated aqueous HCl (1.1 ml) was stirred at room temperature for 2 days. The solvent was evaporated and was replaced with fresh dioxane (3.3 ml) and concentrated aqueous HCl (3.3 ml). Stirring is continued additionally for 2 days, until complete disappearance of starting material. The solvents were removed under vacuum, the residue was distributed between EtOAc (30 ml) and saturated aqueous NaHCO3(30 ml). The aqueous phase was separated and acidified with concentrated aqueous HCl. The product was treated with EtOAc (30 ml), the organic phase was separated and washed with saturated saline (20 ml). The solution was dried over Na2SO4 , was filtered and was evaporated with the formation of compound (71) (120 mg, 72%).1H-NMR (DMSO-d6, TMS) δ: 2.79 (2H, m); 4.10 (1H, m); 4.90 (1H, d, 9 Hz); 7.45 (5H, s), 7.5-7.8 ppm (4H, m).

Synthesis 299

2-(1,1-Dioxo-2-phenyl-2,3-dihydro-1H-benzo[b]thiophene-3-yl)-N-hydroxyacetamido (72)

To a solution of carboxylic acid (71) (120 mg, 0.4 mmol) in CH2Cl2(2 ml) was added chloride oxalic acid anhydride (0.17 ml, 2 mmol) and a drop of DMF. The resulting mixture was stirred at room temperature and was evaporated. To the residue was added a mixture prepared by dissolving hydrochloric salt of hydroxylamine (347 mg, 5 mmol) in a mixture of THF (5 ml) and 1M aqueous NaHCO3(5 ml). The resulting suspension was stirred for 1 hour and was distributed between EtOAc (20 ml) and water (20 ml). The organic phase was separated and washed with saturated NaHCO3(10 ml) and saturated saline (10 ml), the solution was dried over Na2SO4, was filtered and was evaporated. The residue was led from EtOAc with the formation of hydroxamic acid (72) (22 mg, 17%) as colorless crystals with melting point 113-114°C.1H-NMR (DMSO-d6, TMS) δ: 2.2-2.7 (2H, m, overlapping with DMSO); 4.13 (1H, m); 5.05 (1H, d, 8 Hz); 7.3-7.9 (N, m); 8.9 (1H, br s) and 10.6 ppm (1H, br s).

Synthesis 300

Phenylamide 2-iodine-pyridine-3-sulfonic acid (74)

Following the method similar to Method L (glycinate compounds (45)) from sulfonamida (73), received the connection specified in the header in the form of a crude product.

Synthesis 301

Methyl ether (1,1-dioxo-2-phenyl-2,3-dihydro-1H-isothiazole[4,5-b]pyridine-3-yl)acetic acid (75)

Following the method similar to Method M (for the synthesis of compounds (46)) of the iodide (74), was received on the connection specified in the header in the form of a crude product.

Synthesis 302

(1,1-Dioxo-2-phenyl-2,3-dihydro-1H-isothiazole[4,5-b]pyridine-3-yl)acetic acid (76)

Following the method similar to Method E (for synthesis (4)) of the complex ether (75), received the connection specified in the header in the form of a crude product.

Synthesis 303

(1,1-Dioxo-2-phenyl-2,3-dihydro-1H-isothiazole [4,5-b]pyridine-3-yl)acetic acid (77)

Following the method similar to Method G (for synthesis (5)), carboxylic acid (76), was received on the connection specified in the header. A 30%yield, melting point: 123-128°C,1H-NMR (DMSO-d6, TMS) δ: 2.37 (1H, dd, overlapping with DMSO, J=14.9 8.4 Hz); 2.71 (1H, dd, overlapping with DMSO, J=14.9 4.0 Hz); 5.87-5.65 (1H, m); 7.45-7.31 (1H, m); 7.67-7.45 (4H, m); 7.95-7.79 (1H, m), 8.17 (1H, d, J=7.7 Hz); 9.02-8.77 (2H, m) and 10.48 ppm (1H, s).

Biological methods of analysis

System analysis TAS

The activity of compounds as inhibitors of TACE were determined using commercially available is atiny substrate (M-2255, Bachem UK Ltd, St. Helens, UK) and recombinant enzyme TACE (930-ADB, R and D Systems, Abingdon, UK). The recombinant enzyme TACE man (5 ng/30 µl) were incubated for 3.5 hours at 37°C in buffer test (25 mm Tris. HCl, 2.5 μm ZnCl2, of 0.005% Brij 35, pH 8.0) at a substrate concentration of 5 ám in the presence of the test compound (inhibitor of TACE). The degree of TACE activity was determined by measuring fluorescence (excitation at 355 nm, emission at 460 nm).

The activity, expressed in percent (% activity) in each test was calculated as follows:

% activity = {(SC-In)/(S°)}×100

where SCdenotes signal measured in the presence of the enzyme and test compound, S° denotes signal measured in the presence of the enzyme, but in the absence of the test compound, and In denotes the background signal in the absence of the enzyme, and the test compounds. The value of the IC50corresponds to the concentration at which achieved 50% of the activity.

Research selectivity: activity against HDAC (histone deacetylase): analysis by fluorescence

Alternatively, the activity of the compounds as HDAC inhibitors was determined using a commercially available kit for analysis of fluorescence (Fluor de Lys™, BioMol Research Labs, Inc., Plymouth Meeting, USA). Extract of HeLa cells were incubated for 1 hour at 37°C in buffer test (25 mm HEPES, 4-(2-HYDR shall xitil)piperazine-1-econsultancy acid, 137 mm NaCl, 2.7 mm KCl, 1 mm MgCl2, pH 8.0) with 15 µmol acetylated substrate in the presence of the test compound (inhibitor HDAC). The degree of dezazetilirovanie was determined by adding 50 ál component developer dilution 1 : 500, followed by measuring fluorescence (excitation at 355 nm, emission at 460 nm), in accordance with the instructions attached to the kit.

Extract of HeLa cells

Extract of HeLa cells prepared from HeLa cells (ATSC Ref. No.CCL-2) by three freeze-thawing in 60 mm .HCl, pH 8.0, 450 mm NaCl, 30% glycerol. Used buffer for extraction in the dual with respect to the cell volume, and the solid particulate material was centrifuged (20800 g, 4°C, 10 minutes) and discard. Extract the supernatant with deacetylase activity was divided into aliquots and frozen for storage.

The activity, expressed in percent (% activity) for each of the test compounds was calculated as follows:

% activity = {(SC-In)/(S°)}×100

where SCdenotes signal measured in the presence of the enzyme and test compound, S° denotes signal measured in the presence of the enzyme, but in the absence of the test compound, and In denotes the background signal in the absence of the enzyme, and the test compounds. The value of the IC50corresponds to the concentration at which dostigaet is 50% of the activity.

Measurement of cell viability in the presence of the test compounds at increasing concentrations at different points in time were used to assess both the cytotoxicity and the influence of the compounds on cell proliferation.

Biological data

The tables below show the values of the IC50in the analysis with TACE for some compounds according to the present invention.

Data on the inhibition of TACE and HDAC
Identification numberThe connection numberThe average inhibition of TACE EU50(µm)The average inhibition of HDAC EU50(µm)
IX-0015.10,24210%@100
IX-002(+)-(S)-5.14,5443%@100
IX-003(-)-(R)-5.10,2744%@100
IX-0045.21,132%@100
IX-005 5.3of 6.71
IX-0065.43,39
IX-0075.55,52
IX-0085.650%@100
IX-0095.752%@10024%@100
IX-0105.80,3417%@100
IX-0115.986%@100
IX-0125.10,5111%@100
IX-0135.1193%@100
IX-0145.1281%@10
IX-0155.1354%@100
IX-0165.141,33
IX-0175.1597%@100

Data on the inhibition of TACE and HDAC
Identification numberThe connection numberThe average inhibition of TACE EU50(µm)The average inhibition of HDAC EU50(µm)
IX-0185.160,62
IX-0195.1755%@100
IX-0205.180,42-2%@100
IX-0215.19to 6.67
IX-0225.22,16
IX-0235.21 1
IX-0245.2250%@100
IX-0255.233,14
IX-0265.240,55
IX-0275.250,27
IX-0285.262,19
IX-0295.2710,76
IX-0305.2854%@100
IX-0315.2970%@100
IX-0325.310,08
IX-0335.317,42
5.3236%@100
IX-0355.330,47
IX-0365.340,27-4%@100
IX-0375.353,78
IX-0385.361,41
IX-0395.3728%@10
IX-0405.3828%@100
IX-0415.396,01
IX-0425.47,22
IX-0435.4179
IX-0445.420@2
IX-0455.430,006338%@100
IX-046(+)-5.430,27
IX-047(-)-5.430,0031
IX-0485.440,0003819%@100

Data on the inhibition of TACE and HDAC
Identification numberThe connection numberThe average inhibition of TACE EU50(µm)The average inhibition of HDAC EU50(µm)
IX-049(+)-5.440,06
IX-050(-)-5.44less than 0,0001
IX-0515.4581%@100
IX-052 5.4653%@100
IX-0535.471,46
IX-0545.481,38
IX-0555.493,37
IX-0565.5to 4.98
IX-0575.510,08
IX-0585.520,037
IX-0595.530,058
IX-0605.540,48
IX-0615.551,26
IX-0625.560,0085
IX-0635.57less than 0,0001
IX-0645.58less than 0,0001
IX-0655.590,011
IX-0665.60,41
IX-0675.610,52
IX-0685.620,3144%@100
IX-0695.633,38
IX-0705.64to 6.88
IX-0715.6510%@2
IX-0725.6615%@2
IX-0735.67 32%@2
IX-0745.6810%@2
IX-0752464%@1002%@100
IX-076290,23
IX-077360,12
IX-078390,4123,7

Data on the inhibition of TACE and HDAC
Identification numberThe connection numberThe average inhibition of TACE EU50(µm)The average inhibition of HDAC EU50(µm)
IX-079434%@2
IX-08048.10,94
IX-081 48.20,72
IX-08254.135%@2
IX-08354.26,39
IX-08454.30%@2
IX-08554.457%@2
IX-08654.520%@2
IX-08754.61
IX-08854.734@2
IX-08954.80@2
IX-09054.910@2
IX-09154.113@2
IX-09254.1123@2
IX-09354.1229@2
IX-0945726%@100
IX-09562.138%@100
IX-09662.227%@100
IX-097721,0720%@100
IX-098773,85
IX-0994.19%@100
IX-1004.4350%@100
IX-1014.448,59

Some compounds were tested in the same concentration with respect to the set of meta is Loprais matrix, including the enzyme that converts angiotensin (ACE), and determined the inhibition percentage. The data summarized in the table below.

Inhibition of metalloprotease matrix (MMPs)
EnzymeInhibition, % @ 5 micron
IX-001IX-045IX-048
MMP-10-46
MMP-21910-3
MMP-311134
MMP-70-531
MMP-8302113
MMP-919-2-8
MMP-100 69
MMP-12563749
MMP-1324-12-10
MMP-14204
ACE6-8-4

These data show that within the class of compounds derived BCSAs disclosed in the description of the present invention, it is possible to achieve improved selectivity of inhibitors of TACE compared with the related Zn-metalloproteases, such as histone deacetylases or matrix metalloprotease. Therefore, it is expected that the possible application of these inhibitors of TACE without side effects, which are due to inhibition of HDAC or MMD.

In the above description described the principles, preferred options of implementation and the methods of implementation of the present invention. However, as discussed private implementations should not be interpreted as restrictive of the scope of the claims according to the present invention. Instead, the embodiments described above SL is blowing rassmatrivati as illustrative and and not restrictive, and should take into account changes in the implementation that could be done by the workers, who are specialists in this field without departing from the scope of the claims of the present invention.

LINKS

For a more complete description and disclosure of the inventive concept above cited several patents and publications in the field of knowledge that applies the present invention. Listed below are the full references to these publications. The content of each of these references is introduced in the description of this application in its entirety, to the same extent, as if it was stated that each individual publication specifically and individually introduced by reference.

1. A compound selected from compounds of the following formula, and pharmaceutically acceptable salt, hydrate and solvate the specified connection:

in which each of RPW, -RPX, -RPYand RPZindependently represents-H or-RRS1;
each RRS1independently represents-F, -Cl, -Br, -I, -RA1, -CF3, -OH, -OCF3orA1; each RA1independently represents a C1-4alkyl, phenyl or benzyl; and optionally two adjacent groups RRS1together the way the VAT-OCH 2O-, -OCH2CH2O -, or-OCH2CH2CH2O-;
-RAKindependently represents a covalent bond, -(CH2)- or -(CH2)2-; -RNindependently represents-RNNNor-LN-RNNN;
LN- independently represents-CH2- or-CH2CH2-;
RNNNindependently represents a phenyl, naphthyl or pyridyl, and possibly substituted by one or more substituent RS;
each RSis an independently-F, -Cl, -Br, -I, -RD1, -RE7, -RE8, -CF3, -CH2CF3, -CF2CF2H, -OCF3, -OCH2CF3, -OCF2CF2H, -OH, -ORD1, -L1-OH, -
L1-ORD1, -SRD1,-SCF3, -NH2-The otherD1,-NRN1RN2, -O-L1-NH2, -O-L1-OtherD1,, -O-L1-NRN1RN2, -O-RE2, -O-RE3, -O-L3-RE7or-O-L3-RE8;
each-L1represents a saturated aliphatic C1-5alkylen;
each group-NRN1RN2independently represents pyrrolidino, piperidino, or morpholino, and possibly substituted by one or more C1-3alkyl group;
each RD1independently represents a saturated alifaticheskii1-6alkyl, phenyl or benzyl:
ka is ery-R E2independently represents an aliphatic C2-6alkenyl and possibly substituted by one or more-HE, ORF1, -NH2, -NH RF1,and-NRN3RN4;
each RE3independently represents an aliphatic Cz-s quinil and possibly substituted by one or more-HE, ORF1, -NH2, -NH RF1,and-NRN3RN4;
each RE7independently represents phenyl and possibly substituted by one or more-F, -Cl, -Br, -I, - RF1, -OH, -ORF1, -NH2, -NH RF1,and-NRN3RN4;
each RE8independently represents furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, isothiazolin, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, chinoline or ethenolysis and possibly substituted by one or more-F, -Cl, -Br, -I, - RF1, -OH, -ORF1, -NH2, -NH RF1,and-NRN3RN4;
each-L3independently represents a saturated aliphatic C1-3alkylen;
where each RF1independently represents a saturated aliphatic C1-4alkyl, phenyl or benzyl; and
each group-NRN3RN4independently represent pyrrolidino, piperidino, piperazino or morpholino and possibly substituted by one or is m ore than C 1-3the alkyl.

2. The compound according to claim 1, characterized in that:
each of RPW, -RPX, -RPYand RPZrepresents-N.

3. The compound according to claim 1, wherein-RAKrepresents -(CH2)- or -(CH2)2-.

4. The compound according to claim 1, wherein-RAKrepresents -(CH2)-.

5. The compound according to claim 2, wherein-RAKrepresents -(CH2)-.

6. The compound according to claim 1, wherein-RNindependently represents-RNNN.

7. The compound according to claim 2, wherein-RNindependently represents-RNNN.

8. The compound according to claim 4, wherein-RNindependently represents-RNNN.

9. The compound according to claim 5, wherein-RNindependently represents-RNNN.

10. The compound according to claim 2, wherein-RNindependently represents-LN-RNNN.

11. The compound according to claim 1, wherein-RNNNrepresents phenyl and possibly substituted by one or more Deputy-RS.

12. Connection pop, wherein-RNNNrepresents phenyl and possibly substituted by one or more Deputy-RS.

13. The compound according to claim 5, wherein-RNNNrepresents phenyl and possibly substituted by one or more the Deputy-R S.

14. The connection according to claim 9, wherein-RNNNrepresents phenyl and possibly substituted by one or more Deputy-RS.

15. The compound according to claim 1, wherein-RNNNrepresents phenyl and possibly substituted by one or more Deputy-R8and each Deputy-RSindependently represents-F, -Cl, -Br, -I, -RD1, -CF3, -CH2CF3, -CF2CF2H, -OH, -ORD1, -L1-OH, -L1-ORD1, -OCF3, -OCH2CF3, -OCF2CF2H-SRD1, -SCF3, -NH2-The otherD1, -NRD1, -NRN1RN2, -O-L1-NH2, -O-L1-OtherD1,or-O-L1-NRN1RN2.

16. The compound according to claim 2, wherein-RNNNrepresents phenyl and possibly substituted by one or more Deputy-RSand each Deputy-RSindependently represents-F, -Cl, -Br, -I, -R, -CF3, -CH2CF3, -CF2CF2H, -OH, -ORD1, -L1-OH, -L1-ORD1, -OCF3, -OCH2CF3, -OCF2CF2H-SRD1, -SCF3, -NH2-The otherD1, -NRD1, -NRN1RN2, -O-L1-NH2, -O-L1-OtherD1,or-O-L1-NRN1RN2.

17. The compound according to claim 5, wherein-RNNNrepresents phenyl and in which can be substituted by one or more Deputy-R Sand each Deputy-RSindependently represents-F, -Cl, -Br, -I, -RD1, -CF3, -CH2CF3, -CF2CF2H, -OH, -ORD1, -L1-OH, -L1-ORD1, -OCF3, -OCH2CF3, -OCF2CF2H-SRD1, -SCF3, -NH2-The otherD1, -NRD1, -NRN1RN2, -O-L1-NH2, -O-L1-OtherD1,or-O-L1-NRN1RN2.

18. The connection according to claim 9, wherein-RNNNrepresents phenyl, possibly substituted by one or more Deputy-RSeach Deputy-RSindependently represents-F, -Cl, -Br, -I, -RD1, -CF3, -CH2CF3, -CF2CF2H, -OH, -ORD1, -L1-OH, -L1-ORD1, -OCF3, -OCH2CF3, -OCF2CF2H-SRD1, -SCF3, -NH2-The otherD1, -NRD1, -NRN1RN2, -O-L1-NH2, -O-L1-OtherD1,or-O-L1-NRN1RN2.

19. The compound according to claim 1, wherein-RNNNrepresents phenyl and possibly substituted in the para-position of Deputy-RSand not substituted for other provisions.

20. The compound according to claim 2, wherein-RNNNrepresents phenyl and possibly substituted in the para-position of Deputy-RSand not substituted for the rest the provisions.

21. The compound according to claim 5, wherein-RNNNrepresents phenyl and possibly substituted in the para-position of Deputy-RSand not substituted for other provisions.

22. The connection according to claim 9, wherein-RNNNrepresents phenyl and possibly substituted in the para-position of Deputy-RSand not substituted for other provisions.

23. The compound according to claim 1, wherein-RNNNrepresents phenyl and possibly substituted in the para-position-RSand not substituted for other provisions, and RSrepresents-O-RE2or-O-RE3.

24. The compound according to claim 2, wherein-RNNNrepresents phenyl and possibly substituted in the para-position-RSand not substituted for other provisions, and RSrepresents-O-RE2or-O-RE3.

25. The compound according to claim 5, wherein-RNNNrepresents phenyl and possibly substituted in the para-position-RSand not substituted for other provisions, and RSrepresents-O-RE2or-O-RE3.

26. The connection according to claim 9, wherein-RNNNrepresents phenyl and possibly substituted in the para-position-RSand not substituted for other provisions, and RSrepresents-O-RE2or-O-RE3.

27. The compound according to claim 1, characterized those who, that-RNNNrepresents phenyl and possibly substituted in the para-position-RSand not substituted for other provisions, and RSrepresents-O-L3-RE7or-O-L3-RE8.

28. The compound according to claim 2, wherein-RNNNrepresents phenyl and possibly substituted in the para-position-RSand not substituted for other provisions, and RSis a O-L3-RE7or-O-L3-RE8.

29. The compound according to claim 5, wherein-RNNNrepresents phenyl and possibly substituted in the para-position-RSand not substituted for other provisions, and RSis a O-L3-RE7or-O-L3-RE8.

30. Connection pop, wherein-RNNNrepresents phenyl and possibly substituted in the para-position-RSand not substituted for other provisions, and RSrepresents-O-L3-RE7or-O-L3-RE8.

31. The compound according to claim 1, selected from the following compounds and their pharmaceutically acceptable salt, hydrate and solvate:






























32. Pharmaceutical composition for the treatment of
rheumatoid arthritis; inflammation; psoriasis; septic shock; transplant rejection; cachexia; anorexia; congestive heart failure; postischemic reperfusion injury; inflammatory diseases of the Central nerve of the second system; inflammatory bowel disease; insulin resistance; HIV (human immunodeficiency virus); cancer; chronic obstructive pulmonary disease (COPD) or asthma, osteoarthritis, ulcerative colitis, Crohn's disease, multiple sclerosis or degenerative loss of cartilage, which contains a compound according to any one of claims 1 to 31 and a pharmaceutically acceptable carrier, diluent or excipient.

33. A method of obtaining a pharmaceutical composition, comprising mixing the compound according to any one of claims 1 to 31 and a pharmaceutically acceptable carrier, diluent or excipient.

34. The compound according to any one of claims 1 to 31 for use in the treatment of:
rheumatoid arthritis; inflammation; psoriasis; septic shock; transplant rejection; cachexia; anorexia; congestive heart failure; postischemic reperfusion injury; inflammatory diseases of the Central nervous system, inflammatory bowel disease; insulin resistance; HIV (human immunodeficiency virus); cancer; chronic obstructive pulmonary disease (COPD) or asthma, osteoarthritis, ulcerative colitis, Crohn's disease, multiple sclerosis or degenerative loss of cartilage.

35. The use of compounds according to any one of claims 1 to 31 in the manufacture of a medicinal product for treatment:
rheumatoid arthritis; inflammation; PS is riaza; septic shock; transplant rejection; cachexia; anorexia; congestive heart failure; postischemic reperfusion injury; inflammatory diseases of the Central nervous system, inflammatory bowel disease; insulin resistance; HIV (human immunodeficiency virus); cancer; chronic obstructive pulmonary disease (COPD) or asthma; or osteoarthritis, ulcerative colitis, Crohn's disease, multiple sclerosis or degenerative loss of cartilage.

36. Method of treatment:
rheumatoid arthritis; inflammation; psoriasis; septic shock; transplant rejection; cachexia; anorexia; congestive heart failure; postischemic reperfusion injury; inflammatory diseases of the Central nervous system, inflammatory bowel disease; insulin resistance; HIV (human immunodeficiency virus); cancer; chronic obstructive pulmonary disease (COPD) or asthma, or arthritis, ulcerative colitis, Crohn's disease, multiple sclerosis or degenerative loss of cartilage, comprising the administration to a patient in need of treatment a therapeutically effective amount of a compound according to any one of claims 1 to 31.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to 3-aza-bicyclo[3.3.0]octane derivatives of formula , where R1 and R2 are hydrogen, C1-4alkyl or fluorine; R3 is a phenyl which is unsubstituted, mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, C1-4alkoxy group, trifluoromethyl, trifluoromethoxy group and halogen; 2,3-dihydrobenzofuranyl; 2,3-dihydrobenzo[1,4]dioxynyl; or isoxazolyl, pyridyl, indazolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, pyrrolo[2,1b]thiazolyl, imidazo[ 1,2-a]pyridinyl or imidazo[2,1-b]thiazolyl, where said groups are unsubstituted, mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, C1-4alkoxy group, halogen and trifluoromethyl; A is or ; R4 is C1-4alkyl or -NR6R7; R6 is hydrogen or C1-4alkyl; R7 is hydrogen or C1-4alkyl; and D is a phenyl which is unsubstituted, mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, C1-4alkoxy group, trifluoromethyl and halogen; or a pharmaceutically acceptable salt of such a compound. 3-aza-bicyclo[3.3.0]octane derivatives or a pharmaceutically acceptable salt thereof are used as a medicinal agent having the activity of orexin receptor antagonists.

EFFECT: novel 3-aza-bicyclo[3,3,0]octane derivatives as nonpeptide antagonists of human orexin receptors.

9 cl, 1 tbl, 85 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new antibacterial compounds of formula I

wherein R1 represents halogen or alkoxy group; each U and W represents N; V represents CH, and R2 represents H or F, or each U and V represents CH; W represents N, and R2 represents H or F, or U represents N; V represents CH; W represents CH or CRa, and R2 represents H, or also when W represents CH, may represent F; Ra represents CH2OH or alkoxycarbonyl; A represents group CH=CH-B, a binuclear heterocyclic system D, phenyl group which is mono-substituted in the position 4 by C1-4 alkyl group, or phenyl group which is di-substituted in positions 3 and 4 wherein each of two substitutes is optionally specified in a group consisting of C1-4 alkyl and halogen; B represents mono- or di-substituted phenyl group wherein each substitute is a halogen atom; D represents group

wherein Z represents CH or N, and Q represents O or S; or to salts of such compounds.

EFFECT: compounds are used for treating bacterial infections.

13 cl, 2 tbl, 25 ex

FIELD: medicine.

SUBSTANCE: invention refers to an agent for activation of lipoprotein lipase containing a benzene derivative of general formula (1) which is used for preventing and treating hyperlipidemia and obesity. The invention also refers to the benzene derivatives of general formula (1a).

EFFECT: composition improvement.

8 cl, 6 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: method is realised by mixing a compound of formula (B) with p-toluenesulphonic acid or a monohydrate of toluenesulphonic acid in less than 1 molar equivalent with respect to the compound of formula (B), in a solvent while heating. An additional amount of p-toluenesulphonic acid or monohydrate of p-toluenesulphonic acid is then added to the mixed solution while cooling in such an amount that their total molar equivalent with p-toluenesulphonic acid or monohydrate of p-toluenesulphonic acid at the mixing step is equal to 1 molar equivalent or more with respect to the compound of formula (B). At the last step, the obtained solution is crystallised to separate a compound of formula (A).

EFFECT: obtaining a compound of formula (A) with stable high output.

12 cl, 1 dwg, 3 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention describes the pyrrolo- and thiazolopyridinium compounds and their pharmaceutically acceptable salts covered by general structural formula I: wherein the values A, B, R1, R2, R3, R4, R5, R6, R7 and R8 are those as presented in cl.1, and a pharmaceutical composition based on the given compound for inhibition of hypoxia-inducible factor (HIF) hydroxylase activity.

EFFECT: there are produced and described new compounds able to modulate hypoxia-inducible factor (HIF) stability and/or activity.

29 cl, 178 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I , and pharmaceutically acceptable salts thereof, where L denotes O, S, or CH2; Y denotes N or CH; Z denotes CR3; G denotes CH; R1 denotes a heteroaryl ring of formula , where D1 denotes S, O; D2 denotes N or CR12; D3 denotes CR12; R2 denotes (C6-C10)-aryl; 5-9-member mono- or bicyclic heteroaryl with 1 or 2 heteroatoms independently selected from N or S; a saturated or partially saturated (C3-C7)-cycloalkyl; or a saturated 5-6-member heteocyclyl with 1 heteroatom selected from N, where said aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted with one or two groups independently selected from (C1-C6)-alkyl, F, Cl, Br, CF3, CN, NO2, OR6, C(-O)R6, C(=O)OR6, C(=O)NR6R7, saturated 6-member heterocyclyl with 2 heteroatoms independently selected from N or O, and S(O)2R6, and where said alkyl is optionally substituted with one -OR8 group; R3 denotes H; (C1-C6)-alkyl; (C2-C6)-alkenyl; Cl; Br; OR6; SR6; phenyl; or a 6-member heteroaryl with 1 heteroatom selected from N, where said alkyl and alkenyl are optionally substituted with one group selected from C(=O)OR8, -OR8, -NR8R9; or a saturated 6-member heterocyclyl with 1 heteroatom selected from N or O.

EFFECT: disclosed compounds are used in treating and preventing diseases mediated by insufficient level of glucokinase activity, such as sugar diabetes.

16 cl, 479 ex

FIELD: chemistry.

SUBSTANCE: described are novel benzotriazole UV-absorbers, having absorption spectrum shifted towards the long-wave side with considerable absorption in the region up to 410-420 nm, having general formulae (a)-(k) (structural formula and values of radicals are given in the description), composition which is stabilised with respect to UV radiation and containing novel UV-absorbers, and use of the novel compounds as UV light stabilisers for organic materials.

EFFECT: obtaining novel benzotriazole UV-absorbers, having absorption spectrum shifted towards the long-wave side.

13 cl, 23 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted pyrimidine derivatives, having HIV replication inhibiting properties, or pharmaceutically acceptable salts thereof. In formula (1): R1 denotes hydrogen; R2 and R3 independently denote hydrogen; R7 and R8 denote C1-6alkyl; R4 denotes cyano; R9 denotes C1-6alkyl optionally substituted with cyano, C2-6alkenyl substituted with cyano, C2-6alkynyl optionally substituted with cyano; R5 denotes C1-6alkyl optionally substituted with Ar or Het; C2-6alkenyl optionally substituted with Ar or Het; C2-6alkynyl optionally substituted with Ar or Het; C3-7cycloalkyl; Ar; Het; R6 denotes H, Het; Y denotes -OR11, -NR12R13; R11 denotes hydrogen or C1-6alkyl optionally substituted with hydroxy, C1-6alkoxy or pyridyl; R12 denotes hydrogen or C1-6alkyl; R13 denotes hydrogen or C1-6alkyl; or R12 and R13 together with a nitrogen atom, which is substituted by said two substitutes, form a morpholinyl; imidazolyl; X denotes -NR1-; Het denotes 5- or 6-member completely saturated ring, where one or two ring members are heteroatoms, each independently selected from nitrogen and sulphur, and where the rest of the ring members are carbon atoms; and where any member of the heterocycle with a nitrogen heteroatom can optionally be substituted with C1-6alkyl; where the 5- or 6-member ring can optionally be annelated with a benzene or thiophene ring; each aryl independently denotes phenyl or phenyl substituted with one substitute selected from C1-6alkoxy.

EFFECT: high efficiency of using said compounds.

7 cl, 4 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: there are described substituted imidazo[2,1-b]thiazoles of general formula the R1, R1, R3 R4, M1, M2 radical values are presented in the patent claim cl. 1, as well as methods for making them, drug preparations containing these compounds and application of these compounds for making the drug preparations.

EFFECT: higher efficacy.

23 cl, 3 tbl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula

wherein: m, n, R0, R1, R2, R3 and R4 have the values presented in clause 1 of the patent claim provided the compound of formula (I) cannot represent N-methyl-1-(phenylsulphonyl)-1H-indole-4-methanamine.

EFFECT: compounds show 5-NT6 receptor antagonist activity that that allows them being used in the pharmaceutical composition.

19 cl, 3 tbl, 192 ex

FIELD: medicine.

SUBSTANCE: in claimed invention described is compound of general formula 1, or its pharmaceutically acceptable salt, where in each case independently on each other m equals 0, 1; p equals 1 or 2; R1 is selected from group, including -OH, -OC(O)NHMe, -OC(O)NMe2, -OC(O)NH(CH2)2Ph and OC(O)NH(CH2)2NMe2; R2 stands for -OH, -OC(O)Me, -OCH2CO2H, -OCH2CO2Et, -N3, -N=C(NMe2)2, -NH2, -NMe2, -NHC(O)Me, -NHC(O)CF3, - NHC(O)Ph, -NHC(O)NHPh, -NHC(O)CH2CH2CO2H, -NHC(O)CH2CH2CO2Me, - NHCH2Ph, -NHCH2(4-pyridyl), -NHCH2(2-pyridyl), -NHCH2(4-(CO2H)Ph), - NHCH2(3-(CO2H)Ph), -NHEt, -NHCHMe2, -NHCH2CHMe2, -N(CH2CHMe2)2, - NHCH2(cyclopropyl) or -NHC(O)CH2CH2NMe2; R3 stands for -OMe, -OEt, - OCH2(cyclopropyl), F, -O(CH2)2NMe2 or -O(CH2)2(4-morpholino); R4 stands for -NMe2, -NEt2, -NHEt, -NHCH2CHMe2, -N(Me)CH2CHMe2, - N(Me)CH2CH2NHS(O)2Me, -N(Me)CH2CH2NHS(O)2CF3, -NHCH2CH2OH, - N(Me)CH2CH2OH, -N(Me)CH2CO2H, -N(Me)CH2C(O)NH2, N(Me)CH2C(O)NHMe, -N(Me)CH2C(O)NMe2, -NHC(O)Me, 1-piperidinyl, 4-morpholino, (R)-2-(hydroxymethyl)-1-pyrrolidinyl, -NH2, -NO2, Br, CI, F, -C(O)Me or -CH2NH2; R5 stands for -OH or -N(R17)(R18); R17 and R18 independently in each case stand for H, (C1-C6)-alkyl, (C5-C7)-aryl-(C1-C6)-alkyl, where said aryl contains from zero to two heteroatoms, (C1-C6)-alkoxy or -[C(R19)(R20)]P-R21 R19 and R20 independently in each case represent H, (C1-C6)-alkyl, (C1-C6)-alkoxy, amino-(C1-C6)-alkyl, acylamino, sulfonylamino, (C5-C7)-aryl, (C5-C7)-aryl-(C1-C6)-alkyl or 3-10-membered heterocyclyl-(C1-C6)-alkyl, containing in ring from one to two heteroatoms; R21 independently in each case represents H, 3-10-membered heterocyclyl, containing in ring one heteroatom, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylsulfonamido or amido; R22 stands for halogen; R23 stands for methyl; R24 stands for methyl and R25 stands for methyl, where said aryl stands for 5-7-membered ring, containing from zero to two heteroatoms, and said aryl or said heterocyclyl can be non-substituted or substituted halogen, (C1-C6)-alkyl or amino. Also described is pharmaceutical composition, possessing inhibiting activity with respect to Bcl-2 and/or Bcl-XL proteins, which includes said compound, also described is method of treating disorder, mediated by Bcl-2 and/or Bcl-XL proteins, which lies in introduction of said compound to patient, who needs such treatment, in therapeutically efficient amount.

EFFECT: increased efficiency of compound application.

41 cl, 6 dwg, 125 ex

New compounds // 2456273

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula: wherein B is specified in a group consisting of pyridine, pyridazine, pyrimidine and oxazole which can be optionally substituted by halogen, C1-7-alkyl or a C1-7-alkoxy group; L1 is specified in a group consisting of -NH-, -C(O)NH- and -NHC(O)-, A means C3-C12-cycloalkyl, C6-C12-aryl, a 4-7-member monocyclic heterocyclic group consisting of 1-3 heteroatoms optionally specified in O N and S, or a bicyclic heterocyclyl specified in a group consisting of benzimidazolyl, benzoxazolyl, benzothiazolyl, wherein cycloalkyl, aryl, mono- or bicyclic heterocyclyl can be optionally substituted by one or more substitutes optionally specified in a group consisting of a cyano group, halogen, an oxo group, C1-7-alkyl, C1-7-halogenalkyl, a C1-7-alkoxy group, C1-7-halogenalkoxy group, an amino group, a di-C1-7-alkylamino group, a C1-7-alkylthio group and C3-8-cycloalkyl, 1-2- means a bivalent residue specified in a group consisting of: - a bivalent alkyl group consisting of 1 to 4 carbon atoms, a bivalent alkenyl group consisting of 2 to 3 carbon atoms, - -C(O)-, - -C(O)-[R4]c-R5- wherein c is equal to 0, and R5 is specified in a group consisting of a bivalent C1-C4-alkyl group optionally substituted by another C1-4-alkyl, a C4-C8-cycloalkyl group, a phenyl group and a 5- or 6-member heterocyclyl group consisting of N heteroatoms, - -C(O)-NH-, - -(CH2)1-3-C(O)-NH-(CH2)1-3-, - -C(O)-NH-R4- wherein R4 is specified in a group consisting of a bivalent C1-C7-alkyl group optionally substituted by another C1-4-alkyl, a cyclohexyl group and a cyclopentyl group, and E is specified in a group consisting of: - COOH, - a ester group of carboxylic acid, or to its pharmaceutically acceptable salts. What is also described is a pharmaceutical composition exhibiting DGAT1 modulatory activity, on the basis of the presented compounds, and also a method of treating pathological conditions or disorders associated with DGAT1 activity.

EFFECT: there are prepared and described new compounds applicable for treating or preventing the pathological conditions or disorders associated with DGAT1 activity.

22 cl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 2,3-substituted pyrazine sulphonamides of formula (I), use thereof in treating allergic diseases, inflammatory dermatosis, immonological disorders and neurodegenerative disorders, as well as pharmaceutical compositions, having CRTH2 receptor inhibiting action and inhibiting chemoattractant receptor, homologous to the molecule expressed on T-helpers 2. in general formula .

A is selected from a group consisting of

, n denotes an integer independently selected from 0, 1, 2, 3 or 4; m equals 1 or 2; B is selected from a group consisting of phenyl or piperazinyl; R1 denotes hydrogen; R2 denotes phenyl, where R2 is optionally substituted with one or more substitutes selected from a group consisting of halogen, cyano, (C1-C6)alkyl; R3 is selected from a group consisting of (C1-C6)alkyl, aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl and (C3-C8)heterocycloalkyl, where each of said (C1-C6)alkyl, aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl and (C3-C8)heterocycloalkyl is optionally substituted with one or more substitutes selected from a group consisting of halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, heteroaryl, aryl, thioalkoxy and thioalkyl, or where said aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl or (C3-C8)heterocycloalkyl can be condensed with one or more aryl, heteroaryl, (C3-C8)cycloalkyl or (C3-C8)heterocycloalkyl groups and can be substituted with one or more substitutes selected from a group consisting of (C1-C6)alkyl, alkoxy, aryl, heteroaryl, carboxyl, cyano, halogen, hydroxy, amino, aminocarbonyl, nitro, sulphoxy, sulphonyl, sulphonamide and trihaloalkyl; R7 is selected from a group consisting of hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, heteroaryl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, carboxyl, cyano, amino and hydroxy; aryl is selected from phenyl or naphthyl; and heteroaryl is selected from pyridyl, indolyl, 3H-indolyl, benzimidazolyl, quinolizinyl.

EFFECT: high efficiency of using the compounds.

4 cl, 10 dwg, 46 ex

FIELD: chemistry.

SUBSTANCE: invention describes isoxazolines of formula (I), in which A denotes C or N; R denotes C1-4 haloalkyl; X denotes identical or different halogens or C1-4 haloalkyl; l equals 0, 1 or 2; Y denotes halogen or C1-4 alkyl, C1-4alkoxy, C1-4haloalkyl, cyano, nitro, amino, C1-4 alkylcarbonylamino, benzoylamino or C1-4 alkoxycarbonylamino; m equals 1 or 1; and G denotes any group selected from heterocyclic groups given in the description, and a method of producing said compounds and use as insecticides for controlling the population of harmful insects or arthropods.

EFFECT: high efficiency of using said compounds.

11 cl, 28 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

, where the dotted line in the 6-member nitrogen-containing ring Z of formula (I) (said ring Z consists of ring atoms numbered 1 to 6) indicates that a double bond is either present in the 3,4-position of the ring Z of formula (I), or a double bond is absent in ring Z of formula (I); and where the double bond may be present in the 3,4-position of the ring Z of formula (I); or: the double may be absent in ring Z of formula (I) if: i) X denotes N or N+-O-, or ii) V denotes -O-CH2-Q-, or iii) W denotes para-substituted phenyl or para-substituted pyridinyl, and V denotes pyrrolidinyl of formula:

X denotes CH, N, or N+-O-; W denotes para-substituted phenyl or para-substituted pyridinyl; V denotes -O-CH2-Q-, where Q is bonded with a group U of formula (I), or V denotes pyrrolidinyl of formula:

U denotes mono-, di-, tri- or tetra-substituted aryl, where the substitutes are independently selected from C1-7-alkyl and halogen; Q denotes a five-member heteroaryl with two or three heteroatoms independently selected from O and N; R1 denotes C1-7-alkyl or cycloalky; R2 denotes halogen or C1-7-alkyl; R3 denotes halogen or hydrogen; R4 denotes C1-7-alkyl-O-(CH2)0-4-CH2-; R'R"N-(CH2)0-4-CH2-, where R' and R" are independently selected from a group consisting of hydrogen, C1-7-alkyl (optionally substituted with one-three fluorine atoms), cyclopropyl (optionally substituted with one-three fluorine atoms), cyclopropyl- C1-7-alkyl (optionally substituted with one-three fluorine atoms) and -C(=O)-R"', where R'" denotes C1-4-alkyl, C1-4-alkoxy, -CH2-CF3, or cyclopropyl; or R12NH-C(=O)·(O)0-1-(CH2)0-4-, where R12 denotes C1-4-alkyl or cyclopropyl; and n equals 0; and salts thereof. The invention also relates to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds having inhibiting effect on renin.

21 cl, 112 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula 1, compounds of formula 5 and pharmaceutically acceptable salts thereof. In formulae 1 5 Y denotes -C(O)-, X denotes -N(R11)-, R1 denotes a residue of formula 1a or 1b - for formula 1 or residue of formulae 5a or 5b - for formula 5 1a 1b 5a 5b, R2 and R7 independently denote H, hydroxyl or (C1-C6)alkyl; R3 and R6 each independently denotes H, hydroxyl or (C1-C6)alkyl; R4 and R5 each independently denotes H or (C1-C6)alkyl; the rest of the radicals are described in the formula of invention. The invention also relates to separate compounds given in the formula of invention, a pharmaceutical composition having Bcl bound protein inhibiting properties, which contains a therapeutically effective amount of the disclosed compound, a method of treating a bc1 mediated disorder, involving introduction of a therapeutically effective amount of the disclosed compound and a method of treating a bc1 mediated disorder involving administration to a patient in need of treatment of an effective amount of camptothecin and therapeutically effective amount of the disclosed compound.

EFFECT: high efficiency of the composition.

84 cl, 12 tbl, 1 dwg, 217 ex

FIELD: chemistry.

SUBSTANCE: invention relates to oxazolidinone derivatives of formula (I) or pharmaceutically acceptable salts thereof, synthesis method thereof and pharmaceutical compositions containing said derivatives which are used as an antibiotic. Oxazolidinone derivatives, where R1 and R1' independently denote hydrogen or fluorine; R2 denotes -OR7, fluorine, monophosphate or metal phosphate; and R7 denotes hydrogen, C1-3alkyl or an acylated amino acid group, where the amino acid is alanine, glycine, proline, proline, isoleucine, leucine, phenylalanine, β-alanine or valine; R3 denotes hydrogen, a C1-4alkyl group which is unsubstituted or substituted cyano, , -(CH2)m-OR7 (m equals 0, 1, 2, 3, 4) or a ketone group. Oxazolidinone derivatives of formula (I) have antibacterial activity against different human and animal pathogens.

EFFECT: oxazolidinone derivatives, having inhibiting activity towards a wide range of bacteria and having low toxicity.

27 cl, 4 tbl, 73 ex

FIELD: chemistry.

SUBSTANCE: disclosed compounds can be used as a medicinal agent which modulates PPARδ (peroxisome proliferator-activated receptor δ). In formula I

, p is equal to 1; L2 is selected from a group which includes -XOX- and -XSX-, where X is independently selected from a group which includes a bond and C1-C4alkylene; R13 is selected from a group which includes halogen, C1-C6alkyl; R14 is selected from a group which includes -XOXC(O)OR17 and -XC(O)OR17, where X denotes a bond or C1-C4alkylene and R17 denotes hydrogen; R15 and R16 are independently selected from a group which includes -R18 and -YR18, where Y is selected from a group which includes C2-C6alkenylene, and R18 is selected from a group which includes C6-C10aryl, pyridinyl, pyrimidinyl, quinolinyl, benzo[b]furanyl, benzoxazolyl, 1,5-benzodioxanyl, 1,4-benzodioxanyl and 3,4-dihydro-2H-benzo[b][1,4]dioxepin; where any of phenyl, pyridinyl, pyrimidinyl, benzoxazolyl in R18 is independently substituted with 1-2 radicals, independently selected from a group which includes halogen, C1-C6alkyl, C2-C7alkenyl, C1-C6alkoxy group, halogen-substituted C1-C6alkyl, halogen-substituted C1-C6alkoxy group, C3-C12cycloalkyl, phenyl, morpholinyl, pyrrolidinyl, piperidinyl, -XNR17R17, -XC(O)NR17R17, -XC(O)R19 and -XOXR19, where X denotes a bond or C1-C4alkylene; R17 is selected from a group which includes C1-C6alkyl, and R19 is selected from a group which includes C3-C12cycloalkyl, piperidinyl and phenyl. The invention also relates to use of the disclosed compounds to prepare a medicinal agent which modulates PPARδ activity, a pharmaceutical composition having PPARδ activity modulating properties, which contains a therapeutically effective amount of the disclosed compound and to use of the pharmaceutical composition in preparing a medicinal agent which modulates PPARδ activity.

EFFECT: improved properties of compounds.

10 cl, 1 tbl, 69 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) or pharmaceutically acceptable salts thereof, having CRP receptor antagonist activity. In formula (I) R1 denotes C3-C8 alkyl, optionally substituted with hydroxyl; phenyl optionally substituted with 1-3 substitutes selected from halogen, nitro, amino, hydroxyl, C1-C4 alkoxy, C1-C4 alkyl, optionally substituted with hydroxyl or C1-C4 alkylamino; naphthyl; C-bonded 5-6-member heteroaryl with 1-2 heteroatoms selected from S, N or O, optionally substituted with C1-C4 alkyl, C1-C4 alkoxy or acetyl; N-bonded 5-member heteroaryl with 1-2 heteroatoms selected from N, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl or phenyl; R2 denotes phenyl, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl, halogenC1-C4alkyl, C1-C4 alkoxy, halogenC1-C4alkoxy, halogen, hydroxy, di(C1-C4 alkyl)amino or di(C1-C4 alkyl)aminocarbonyl; or a heterocyclic group which is pyridyl, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl, C1-C4 alkoxy or di(C1-C4 alkyl)amino; X denotes -NR3-, where R3 denotes C1-C4 alkyl, optionally substituted with hydroxyl, carboxyl or C1-C4 alkoxycarbonyl; Y1 denotes CR3a, where R3a denotes hydrogen, halogen, cyano, hydroxy, C1-C4 alkyl, optionally substituted with hydroxyl or halogen, C1-C4 alkoxy optionally substituted with halogen; Y2 denotes CR3b, where R3b denotes hydrogen or halogen; Y3 denotes N or CR3c, where R3c denotes hydrogen; and Z denotes O or -NR4-, where R4 denotes hydrogen.

EFFECT: invention also pertains to a method of producing compounds of formula (I), a pharmaceutical composition, an inhibiting method, CRF receptor antagonists and use thereof to prepare a medicinal agent.

25 cl, 9 tbl, 163 ex

FIELD: chemistry.

SUBSTANCE: invention relates to (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-cyclopropyl-1 -{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate of formula:

. The invention also relates to salts and solvates of the said compound, a method of producing said compound, a pharmaceutical agent having angiotensin II antagonist activity, based on said compound.

EFFECT: compound can be used in medicine to prevent and treat blood circulatory system diseases.

18 cl, 1 dwg, 8 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (IX) wherein radicals and symbols have values given in the claim, and pharmaceutically acceptable salts or tautomers thereof. Said compounds are inhibitors of poly(ADP-ribose)polymerase (PARP) and can be used to treat cancer, inflammatory diseases, reperfusion injuries, ischaemic conditions, stroke, renal failure, cardiovascular diseases, vascular diseases other than cardiovascular diseases, diabetes mellitus, neurodegenerative diseases, retroviral infections, retinal damage, skin senescence and UV-induced skin damage, and as chemo- or radiosensitisers for cancer treatment. The invention also relates to a pharmaceutical composition containing said compounds, use of said compounds and a method of treating said diseases.

EFFECT: high efficiency of using the compounds.

10 cl, 18 ex

Up!