Substituted azetidinone, the method of production thereof, pharmaceutical composition and method of treatment
(57) Abstract:
The invention relates to substituted azetidinone General formula I listed in the description. The compound of formula I is produced by interaction of the compounds of formula II with H-Y-NR7R8-. The technical result is the compound of formula I is a potent inhibitor of leukocyte elastase person and can be used as anti-inflammatory and antidegradation agents. 5 C. and 28 C.p. f-crystals, 15 tab., 2 schema.We showed that the members of the new group substituted azetidinone are potent elastase inhibitors and therefore can be used as anti-inflammatory and antidegradation agents.There is evidence that protease from granulocytes and macrophages are involved in the mechanisms of chronic tissue destruction associated with inflammation, including events taking place in the case of rheumatoid arthritis and emphysema. Accordingly, specific and selective inhibitors of these proteases can be considered as a potential anti-inflammatory agents with a view to their use for the treatment of inflammatory conditions resulting from the degradation of connective tissue, namely: the, is steoarthritis, spondylitis, lupus, psoriasis, atherosclerosis, sepsis, septicemia, shock, myocardial infarction, reperfusion damage, periodontitis, cystic fibrosis and acute respiratory distress syndrome.The role of proteases from granulocytes, leukocytes or macrophages associated with the implementation of fast-paced series of events during the progressive development of the inflammatory phenomena:(1) there Is a rapid production of prostaglandins (PG) and related compounds, synthesized from arachidonic acid. It was shown that the synthesis of PG inhibited under the influence related to aspirin and nonsteroidal anti-inflammatory agents, including indomethacin and phenylbutazone. There is evidence that the protease inhibitors inhibit the production of GHGs;
(2) in Addition, there is a change in vascular permeability, which causes the leakage of fluid at the site of inflammation with the formation of edema, the emergence of which is commonly used as a marker for expression of the degree of inflammation. It was shown that this process is induced by proteolytic or peptide-splitting activity of proteases, especially those contained in granulocytes, and in this regard, could the and the corresponding 1,1-dioxides. Morris Zimmerman et al., J. Biol. Chem., 255, 9848 (1980) and
(3) the emergence and/or the presence of lymphoid cells, especially macrophages and polymorphonuclear neutrophils (PMA). It is known that macrophages and PMA released many proteases that was a further evidence that proteases play an important role in inflammation.In General, proteases represent an important family of enzymes characterized by the ability to cleavage of the peptide bond, the members of this family are inherent biological activity related to such things as digestion, the formation and dissolution of blood clots, the formation of the active form of the hormone and organisms, and so on, as well as to pathological processes, such as degradation of structural proteins, the connection of the articular cartilage/pannus in rheumatoid arthritis, etc.Elastase is one of the representatives of the proteases. It is an enzyme capable of hydrolysis component of connective tissue, elastin, a property not shown by a variety of proteases present in mammals. The specified enzyme acts on the protein non-end relationship adjacent to the aliphatic amino acid. This allenou against natural substrates of connective tissue. In particular, elastase from granulocytes is a very important enzyme in connection with the fact that, as mentioned above, granulocytes participate during the acute inflammatory process, and also related to an exacerbation of chronic forms of inflammation, characteristic of a large number of clinically important inflammatory diseases.Protease can inaktivirovanie a large number of inhibitors that block the active sites of enzymes by binding with them. Occurring in their natural state inhibitors of proteases form part of the control or protective mechanisms, which is essential for normal functioning of the body. In the absence of such regulatory mechanisms of protease could destroy any protein within their reach. It has been shown that natural inhibitors of the enzyme have suitable configuration that allows them firmly in contact with this enzyme. The existence of such a configuration partially explains the bond strength of inhibitors with the enzyme (see Stroud, "A Family of Protein-Cutting Proteins", SCi. Am. July 1974, pp. 74 - 88).For example, one of the natural inhibitors -1-antitripsin - is a glycoprotein, Sadeh enzymes, the elastase from the pancreas and PMA. This inhibitor is hydrolyzed by proteases with the formation of a stable acyl enzyme, in which the active site becomes unavailable. A pronounced decrease in the content 1-antitrypsin in serum, or associated with genetic causes, or with the action of oxidants, accompanied by emphysema, a disease characterized by progressive loss of lung elasticity, which develops respiratory failure. There are reports that at the heart of this loss easy its elasticity lies progressive, uncontrolled proteolysis or destruction of the structure of lung tissue under the action of proteases, such as elastase released from leukocytes. J. C. Powers, TIBS, 211 (1976).Rheumatoid arthritis is characterized by progressive destruction of articular cartilage, as on the free surface, limiting sustavnoi space, and on eroded land, formed at the expense of serving in the direction of the cartilage of the synovial tissue. The same process of destruction, at the same time, can cause the protein-splitting enzyme elastase, which is a neutral protease present stokesie studies have shown, in the junction of the cartilage/pannus in the case of rheumatoid arthritis there is an accumulation of granulocytes; and
(2) recent studies of the mechanical properties of cartilage, developing in response to exposure of purified elastase showed the direct involvement of enzymes of granulocytes in the first place, elastase, in the process of rheumatoid destruction of cartilage. H. Menninger, et al., in Biological Functions of Proteinases, H. Holzer and H. Tschesche, eds., Springer - Verlag, Berlin, Heidelberg, New York, pp. 196 - 206, 1979.The second aspect of the present invention relates to the use of new azetidinone to treat certain types of cancer, including alymphoplasia leukemia, acute myeloblastic leukemia (FAB FAB M1 and M2), acute promyelocytic leukemia (FAB M3), acute myelomonocytic leukemia (FAB M4), acute monocytic leukemia (FAB M5), erythroleucus, chronic myeloid leukemia, chronic myelomonocytic leukemia, chronic monocytic leukemia and status that accompany leukemia that are associated with involvement in the process activity PMA neutral proteases, such as disseminated intravascular coagulation. We found that disclosed in the present invention substituted azetidinone are inhibitors of proteinase 3(PR-3), known takutin encoded by a single mRNA; D. Campanelli, et al. , J. Exp. Med., vol. 172, 1709 - 1714, (1990). Cloning of cDNA for proteinase 3: serine protease, antibiotic and autoantigen from human neutrophils; and Bories, et al., Cell. vol. 59, 959 - 968 (1989). Down-regulation of serine protease - myeloblastin - stop growth and differentiation of human promyelocytic leukemia cell.Recently, it was shown the involvement of down-regulation of PR-3 in the proliferation and maintenance of differentiation of some leukemia cells. In particular, Bories, et al. showed that the expression of the enzyme, referred to in the present invention as proteinase 3/myeloblastin, subject to inhibition in the processing of HL-60 leukemia cells human antimuslim oligodeoxynucleotides, this treatment induces differentiation of cells and inhibits their proliferation. In addition, we have shown that treatment of HL-60 leukemia cells cell line human leukemia, among others, compounds of the present invention also leads to inhibition of proliferation of these cells and induces their differentiation.On this basis, we believe that the treatment of leukemia, as alymphoplasia leukemia, acute myeloblastic leukemia (FAB FAB M1 and M2), acute promyelocytic leukemia (FAB Msty leukemia, chronic myelomonocytic leukemia, chronic monocytic leukemia and status that accompany leukemia that are involved in the process accunest PMA neutral proteases, in particular, the state of disseminated intravascular coagulation, including the introduction of a therapeutically effective amount of the compounds of formula I leads to remission of the disease. This introduction can be conducted either orally or parenterally.The present invention relates to a specifically substituted azetidinone formula I:
< / BR>It was shown that these substituted azetidinone can be used as anti-inflammatory and antidegradation agents. The present invention relates also to pharmaceutical compositions and methods for using these specific substituted azetidinone. These compounds can be used to treat certain types of leukemia and conditions associated with the development of leukemia.The present invention relates to potent elastase inhibitors of formula I:
< / BR>used for the prevention, control and treatment of inflammatory and degenerative conditions in the first place, such as arthritis and emphysema.
where R represents a C1-6alkyl; R1represents a C1-6alkyl; M represents an ethyl, propyl, butyl, pentyl or hexyl; each of Raand Rbis independently from each other: (1) hydrogen; (2) C1-6alkyl; (3) a hydroxy-group; R2is: (1) hydrogen; (2) C1-6alkyl; (3) holograph; (4) C1-6alkoxy; (5) amino, C2-3allyloxycarbonyl, where the amino group may be mono - or di-substituted C1-6by alkyl; (6) amino, C2-3alkylaminocarbonyl, where the amino group may be mono - or di-substituted C1-6by alkyl; (7) a hydroxy-group; (8) aminocarbonyl, where the amino group may be mono - or di-substituted C1-6by alkyl; (9) hydroxymethyl; (10) aminocarboxylate C1-3alkyl, where the amino group may be mono - or di-substituted C1-6by alkyl; (11) cyano; (12) morpholinosydnonimine; or (13) morpholinoethyl;
R3is: (1) C1-6alkyl; (2) holograph; (3) C1-6alkoxy; (4) amino, C2-3allyloxycarbonyl, where the amino group may be mono - or di-substituted C1-6by alkyl; (5) amino, C2-3alkylaminocarbonyl, where the amino group may be mono - or di-substituted C1-6by alkyl; (6) a hydroxy-group; (7) aminocarbonyl, where the amino group can be moget be mono - or di-substituted C1-6by alkyl; (10) cyano; (11) morpholinosydnonimine, or (12) morpholinoethyl,
provided that R2and R3can be combined with each other to form methylenedioxy;
R4is
< / BR>or
< / BR>where Rxrepresents carboxy C1-6alkyl, benzyloxycarbonyl C1-3alkyl or tert-butoxycarbonyl C1-3alkyl,
where Q represents a covalent bond or a group:
< / BR>where each of R5and R6represents hydrogen; Y represents a
< / BR>or a covalent bond; R12represents hydrogen or C1-3alkyl; R7represents: (a) the ethyl, propyl, butyl, pentyl or hexyl; (b) C1-6alkyloxy C2-3alkyl; (b) hydroxy, C2-6alkyl; (g) polyhydroxy C2-6alkyl; (d) carboxamido C1-6alkyl; (e) C1-6alkanoyl; (g) substituted phenyl or phenyl-C1-6alkyl, and the substituents represented by X1and X2as defined below; (C) C2-6alkenyl; (and) C6-10cycloalkenyl; (K) heteroaryl C1-6alkyl, these heteroaryl includes pyridinyl and imidazolyl; (l) carboxy C1-6alkyl; (m) Carbo-C1-6alkoxy, C1-3alkyl; (n) phenylsulfonyl; (o) C1-6alkylsulfonyl, when this amino group may be mono - or di-substituted C1-6by alkyl; (u) aminocarbonyl, and the amino group may be mono - or di-substituted C1-6by alkyl; (f) aminocarboxylate C2-6alkyl, amino group may be mono - or di-substituted C1-6by alkyl; (x) azabicyclo containing from 7 to 12 atoms; (C) di (C1-3alkylamino C2-6alkyl, amino group may be mono - or di-substituted C1-6by alkyl; (h) bicycloalkyl containing from 7 to 12 atoms; (W) C3-10cycloalkyl, possibly substituted C1-6by alkyl; (y) pyrazolidine; (b) a substituted or an unsubstituted piperidinyl or pyrrolidinyl, where the substituents may be C1-3alkyl, hydroxy-C1-3alkylbenzene, carboxamido - or amino group, the amino group may be mono - or di-substituted C1-6by alkyl; (AA) substituted pyrrolidinyl, in which the Deputy is carboxamido - or amino group, the amino group may be substituted C1-6by alkyl; (BB) pyrimidinyl; (IV) phosphono C1-6alkyl or (gg) alpha-C1-3alkylbenzene, and mono - or di-substituted benzyl or mono - or di-substituted pyridylmethyl, while the substituents are X1or X2;
R8presented is) polyhydroxy C2-6alkyl; (d) carboxamido C1-6alkyl; (e) C1-6alkanoyl; (g) substituted phenyl or phenyl-C1-6alkyl, and the substituents represented by X1and X2as defined below; (C) C2-6alkenyl; (and) C6-10cycloalkenyl; (K) heteroaryl C1-6alkyl, these heteroaryl selected from the group including pyridinyl and imidazolyl; (l) carboxy C1-6alkyl; (m) Carbo-C1-6alkoxy, C1-3alkyl; (n) phenylsulfonyl; (o) C1-6alkylsulfonyl; (p) benzyloxy; (p) morpholinyl C1-3alkylsulfonyl; (C) tetrahydropyranyl; (t) amino, C1-3alkylsulfonyl, amino group may be mono - or di-substituted C1-6by alkyl; (u) aminocarbonyl, and the amino group may be mono - or di-substituted C1-6by alkyl; (f) aminocarboxylate C2-6alkyl, amino group may be mono - or di-substituted C1-6by alkyl; (x) azabicyclo containing from 7 to 12 atoms; (C) di (C1-3alkylamino C2-6alkyl, amino group may be substituted C1-6by alkyl; (h) bicycloalkyl containing from 7 to 12 atoms; (W) C3-10cycloalkyl, possibly substituted C1-6by alkyl; (y) pyrazolidine; (b) a substituted or an unsubstituted piperidinyl, in which the Deputy can the t to be substituted C1-6by alkyl; (AA) substituted pyrrolidinyl, in which the Deputy is carboxamido - or amino group, the amino group may be substituted C1-6by alkyl; (BB) pyrimidinyl; (IV) phosphono C1-6alkyl or (gg) alpha-C1-3alkylbenzene, and mono - or di-substituted benzyl or mono - or di-substituted pyridylmethyl, while the substituents are X1or X2;
While X1represents: (1) hydrogen; (2) holograph; (3) C1-6alkyl; (4) halo, C1-6alkyl; (5) C2-6alkenyl; (6) hydroxy, C1-6alkyl; (7) C1-6alkylsulphonyl; (8) C1-6alkylcarboxylic; (9) CN group; (10) CF3; (11) CH3O; (12) an amino group, this amino group may be mono - or di-substituted C1-6by alkyl; (13) carboxypropyl or (14) vinylsulfonylacetamido;
X2represents hydrogen, halogroup or C1-6alkyl;
n represents the number 1, 2, 3, 4 or 5;
R9selected from the group including hydrogen, C1-4alkyl and C1-3alkoxy, C2-3alkyl; or phenyl, phenyl C1-3alkyl, pyridyl and pyridyl C1-3alkyl;
each of R10and R11chosen independently of one another from the group comprising hydrogen, C1-4alkyl and C1-3TA, to which they are attached, form a mono - or di-substituted ring selected from the group consisting of (1) piperidinyl or homopiperazine; (2) piperazinil; (3) morpholinyl, thiomorpholine or 1,1-dioxo-4-thiomorpholine; (4) pyrrolidinyl; (5) peril; (6) imidazolyl; (7) triazolyl; (8) saturated azabicyclo-group containing from 7 to 12 atoms; (9) azaspiro group; (10) tetrazolyl; (11) pyrazolidine; (12) azetidine or (13) of diazabicyclo-group containing from 7 to 12 atoms, where each of the substituents selected from the group consisting of hydrogen and C1-3of alkyl, benzyloxycarbonyl, phenyl-C1-3alkylaminocarbonyl, pyrrolidinyl, hydroxy, C1-3of alkyl, C1-6alkoxy, C1-4allyloxycarbonyl, aminocarbonyl where the above-mentioned amino group may be mono - or di-substituted C1-6the alkyl, and carbonyl group; or
R8and R9together form a mono - or di-substituted saturated monocyclic ring containing from 6 to 7 atoms comprising 2 nitrogen atom; or
R9and R12together form a mono - or di-substituted saturated monocyclic ring containing 5, 6 or 7 atoms and one nitrogen atom; or
R10and R12together with the carbon atoms to which they are attached, education is sustained fashion the compounds of formula I through p. 1, where Q is a covalent bond; Y is a
< / BR>R4represents a
< / BR>Especially compounds, where R represents a C1-6alkyl; R1represents C1-6alkyl; M represents C1-6alkyl; each of Raand Rbrepresents hydrogen; each of R2and R3is independently from each other: (1) hydrogen; (2) C1-6alkyl;
or R2and R3can be combined with each other to form methylenedioxy;
R4represents a
a)
where Q represents a covalent bond; Y is a
< / BR>R12represents hydrogen or C1-3alkyl; each of R7and R8is independently from each other: (a) hydrogen; (b) C1-6by alkyl; (C) C1-6alkoxy, C2-3by alkyl; (g) hydroxy, C2-3by alkyl; (d) carboxamido C1-6by alkyl; (e) C1-6alkanoyl; (f) phenyl or phenyl C1-6by alkyl; (C) C2-6alkenyl; (and) C6-10cycloalkenyl; (K) heteroaryl C1-6the alkyl, these heteroaryl includes pyridinyl imidazolyl; (l) carboxy C1-6by alkyl; (m) C1-6alkylsulfonyl; (h) benzyloxy; (o) morpholinyl C1-3alkylsulfonyl; (n) amino, Cthe'neil, when this amino group may be mono - or di-substituted C1-6by alkyl; (C) aminocarboxylate C2-6the alkyl, the amino group may be substituted C1-6by alkyl; (t) pyrazolidine; (u) piperidinium; (f) pyrimidinium; (x) alpha-C1-3alkylbenzenes, and mono - or di-substituted benzyl or mono - or di-substituted by pyridylmethyl, while the substituents are X1or X2;
where X1represents: (1) hydrogen; (2) holograph; (3) C1-6alkyl; (4) halo, C1-6alkyl; (5) C2-6alkenyl; (6) hydroxy, C1-6alkyl; (7) C1-6alkylsulphonyl; (8) C1-6alkylcarboxylic; (9) an amino group which may be substituted C1-6by alkyl; or (10) carboxypropyl;
X2represents hydrogen, halogroup or C1-6alkyl;
n represents the number 1, 2, 3, 4, or 5; each of R10and R11chosen independently of one another from the group consisting of hydrogen, C1-4the alkyl and C1-3alkoxy-C1-3of alkyl; or
R7and R8together with the nitrogen to which they are attached, form a mono - or di-substituted ring selected from the group including: (1) piperidinyl; (2) piperazinil; (3) morpholinyl; (4) pyrrolidinyl; (5) peril; (6) imidazolyl; (7) uppy, containing hydrogen and C1-3alkyl, benzyloxycarbonyl, phenyl C1-3alkylaminocarbonyl, hydroxy, C1-3alkyl, C1-6alkoxy, C1-4allyloxycarbonyl and oxoprop; or R10and R12together with the carbon atoms to which they are attached, form a monocyclic mono - or di-substituted ring containing 5, 6 or 7 carbon atoms.One of them should be allocated to the connection, where R represents a C1-3alkyl; R1represents a C1-3alkyl; M represents C1-6alkyl; R2represents: (a) hydrogen; (b) C1-6alkyl; R3represents hydrogen; or R2and R3together with the formation of methylenedioxy; R7and R8independently from each other chosen from the group consisting of: (a) hydrogen; (b) C1-6alkyl; (C) C1-3alkoxy, C2-3alkyl; (d) substituted benzyl in which the substituents are X1and X2while X1represented by hydrogen, and X2represents: (a) hydrogen; (b) galegroup or (b) C1-3alkyl; n represents the number 1, 2 or 3, and
R10and R11chosen independently of one another from the group comprising hydrogen, C1-4alkyl and C1-3alkoxy, C1-3alkyl;
piperazinil and (C) morpholinyl; or R10and R12together with the carbon atoms to which they are attached, form a mono - or di-substituted monocyclic ring containing 5, 6 or 7 carbon atoms.Or compounds where R represents methyl or ethyl; R1represents methyl or ethyl; M represents C1-4alkyl; R2represents: (a) hydrogen; (b) C1-3alkyl, and R3represents hydrogen; or R2and R3together with the formation of methylenedioxy; n represents the number 1 or 2; R10choose from the group consisting of: (a) C1-3alkyl; (b) C1-3alkoxy, C2-3alkyl; (C) hydrogen; R7and R8independently from each other chosen from the group consisting of: (a) hydrogen; (b) C1-3alkyl; (C) C1-3alkoxy-C2-3alkyl;
or R7and R8together with the nitrogen atom to which they are attached, form a substituted ring selected from the group consisting of (a) piperidinyl, and (b) morpholinyl;
or R10and R12together with the carbon atoms to which they are attached, form a mono - or di-substituted monocyclic ring containing 5, 6 or 7 carbon atoms.Among the preferred compounds of formula I include compounds where the organisations, where R represents a C1-6alkyl; R1represents C1-6alkyl; M represents C1-6alkyl; each of Raand Rbrepresents hydrogen; each of R2and R3is independently from each other: (1) hydrogen; (2) C1-6alkyl, or R2and R3can be combined together to form methylenedioxy; R4represents a
< / BR>where Q denotes a covalent bond; or Y is a
< / BR>R12represents hydrogen or C1-3alkyl; each of R7and R8is independently from each other: (a) hydrogen; (b) C1-6by alkyl; (C) C1-6alkoxy, C2-3by alkyl; (g) hydroxy, C2-3by alkyl; (d) carboxamido C1-6by alkyl; (e) C1-6alkanoyl; (f) phenyl or phenyl C1-6by alkyl; (C) C2-6alkenyl; (and) C6-10cycloalkenyl; (K) heteroaryl C1-6the alkyl, these heteroaryl includes pyridinyl imidazolyl; (l) carboxy C1-6the alkyl or Carbo C1-6alkoxy-C1-3by alkyl; (m) C1-6alkylsulfonyl; (h) benzyloxy; (o) morpholinyl C1-3alkylsulfonyl; (n) amino, C1-3alkylsulfonyl, and the amino group may be mono - or di-substituted C1-6by alkyl; (R) aminocarbonyl, when this amino group may be substituted C1-6by alkyl; (t) pyrazolidine; (u) piperidinium; (f) pyrimidinium; (x) C3-7cycloalkyl; (C) alpha-C1-3alkylbenzenes, or mono - or di-substituted benzyl or mono - or di-substituted by pyridylmethyl, while the substituents are X1or X2;
where X1represents: (1) hydrogen; (2) holograph; (3) C1-6alkyl; (4) halo, C1-6alkyl; (5) C2-6alkenyl; (6) hydroxy, C1-6alkyl; (7) C1-6alkylsulphonyl; (8) C1-6alkylcarboxylic; (9) di-C1-3alkylamino or (10) carboxypropyl;
X2represents hydrogen, halogroup or C1-6alkyl;
n represents the number 1, 2, 3, or 4; R9selected from hydrogen, C1-4the alkyl and C1-3alkoxy-C2-3of alkyl; each of R10and R11chosen independently of one another from the group consisting of hydrogen, C1-4the alkyl and C1-3alkoxy-C1-3of alkyl; or R7and R8together with the nitrogen to which they are attached, form a mono - or di-substituted ring selected from the group including: (1) piperidinyl; (2) piperazinil; (3) morpholinyl; (4) pyrrolidinyl; (5) peril; (6) imidazolyl; (7) triazolyl; (8) tetrazolyl; (9) pyrazolidine or (10) shall oxycarbonyl, phenyl C1-3alkylaminocarbonyl, hydroxy, C1-3alkyl, C1-6alkoxy, C1-4allyloxycarbonyl and oxoprop; or R8and R9together form a saturated mono - or di-substituted monocyclic ring containing 6 or 7 carbon atoms and containing 2 nitrogen atom; such ring selected from piperazinil and homopiperazine; or R9and R12together form a mono - or di-substituted saturated monocyclic ring containing 5, 6 or 7 atoms, the said ring consists of one nitrogen atom; or R10and R12together with the carbon atoms to which they are attached, form a mono - or di-substituted monocyclic ring containing 5, 6 or 7 carbon atoms.Or compounds where R represents a C1-3alkyl; R1represents C1-3alkyl; M represents C1-6alkyl; R2represents: (a) hydrogen; (b) C1-6alkyl; R3represents hydrogen; or R2and R3together with the formation of methylenedioxy; R7and R8independently from each other chosen from the group consisting of: (a) hydrogen; (b) C1-3alkyl; (C) C1-3alkoxy, C2-3alkyl; (g) hydroxy, C2-3alkyl; (d) Carbo C1-4alkoxide gorodom, and X2represents: (a) hydrogen; (b) galegroup or (b) C1-3alkyl; n represents the number 1, 2 or 3, and R9, R10and R11are selected independently of one another from the group comprising hydrogen, C1-4alkyl and C1-3alkoxy, C2-3alkyl;
or R7and R8together with the nitrogen atom to which they are attached, form a substituted ring selected from the group consisting of: (a) piperidinyl; (b) piperazinil and (C) morpholinyl; or R8and R9together form a mono - or di-substituted saturated monocyclic ring containing 5, 6 or 7 carbon atoms and containing two atoms of nitrogen.Or compounds where R represents methyl or ethyl; R1represents methyl or ethyl; M is (a) C1-4alkyl; R2represents: (a) hydrogen; (b) C1-3alkyl; R3represents hydrogen or R2and R3together form methylenedioxy; n represents the number 1 or 2; R9and R10choose from the group consisting of: (a) hydrogen; (b) C1-3alkyl; (C) C1-3alkoxy, C1-3alkyl; R7and R8independently from each other chosen from the group consisting of: (a) hydrogen; (b) C1-3alkyl; (C) C1-3alkoxy, C2-3alkyl; (g) Gert mono - or di-substituted monocyclic ring,
which is piperidinyl or morpholinyl, with the said ring may be substituted by hydrogen or stands;
or R8and R9together form a mono - or di-substituted saturated monocyclic ring, which is piperazinil.Another group of compounds are the compounds where Rais: (1) hydrogen; (2) C1-6alkyl; Rbrepresents hydrogen or C1-6alkyl; R2represents: (1) hydrogen; (2) C1-6alkyl; (3) holograph; (4) C1-6alkoxy; R3represents: (1) C1-6alkyl; (2) holograph; or R2and R3can be connected together to form methylenedioxy; R4represents a
< / BR>and R7represents (b) the ethyl, propyl, butyl, pentyl and hexyl; (C) cyclopropyl; (g) C1-3alkoxy, C2-3alkyl; (d) hydroxyethyl; (e) carbetimer; R8represents: (a) C1-3alkyl; (b) cyclopropyl; (C) C1-3alkoxy, C2-3alkyl; (g) hydroxyethyl; (e) carbetimer; or R7and R8together with the nitrogen atom to which they are attached, form a mono - or di-substituted monocyclic ring, which is piperidinyl or morpholinyl, when armuli I include compounds of General formula
< / BR>in which A represents (1) -CH2CH2N(CH3)2; (2) -CH2CO2H; (3) -CH2-C(O)N(CH2CH2OH)2; (4) -CH2-C(O)N(CH3)CH2C(O)NH2; (5) -CH2C(O)NH-(CH2OH)3; (6) -CH2C(O)N(CH3)2; (7) -CH2CH2N(CH3)Ac; (8) -CH(CH3)CO2CH2Ph; (9) -CH(CH3)CO2H; (10) -CH(CH3)C(O)N(Et)2; (11) -CH(CH3)CH3N(CH3)2; (12) -CH2CH2CH2N(CH3)2; (13) -CH2CH2N(Et)2; (14) -CH2CH2(4-morpholinyl);
(15) -CH2CH2CH2CH2N(CH3)2; (16) -CH2C(O)-PrO-NHCH2Ph; (17) -CH2C(CH3)2N(CH3)2; (18) -CH2CH2N(i-Pr)2; (19) -CH2CH2N(n-Bu)2; (20) -CH2CH2CH2CH2CH2CH2N (CH3)2; (21) -CH2CH2(1-piperazinil); (22) -CH2CH2(4-methyl-1-piperazinil); (23) -CH2CH2N(Ph)2; (24) -CH2CH2N(CH2CH= CH2)2; (25) -CH2CH(Ph)N(CH3)2or (26) -CH2CH2N(CH3)CH2Ph.Or the compounds of formula
< / BR>in which A represents (1) -CH2CH2N(CH3)2; (2) CH2CH2CH
or compounds of the second group of the formula
< / BR>in which A represents (1) -N(CH2CH2OH)2; (2) 4-methyl-1-piperazinil; (3) 4-morpholinyl; (4) -NHCH2CH2N(CH3)2; (5) -N(CH3)CH2CH2N(CH3)2; (6) -NHCH2CH2CH2N(CH3)2; (7) -NHCH2CH2(-4-pyridyl); (8) -NHCH2CO2H; (9) -NHCH(CH3)CO2H; (10) -NHCH2C(O)N(CH2CH2OH)2; (11) -N(CH3)CH2CO2H; (12) -NHCH(CH3)C(O)N(CH2CH2OH)2; (13) -N(CH3)CH2C(O)N(CH2CH2OH)2; (14) -N(CH3)CH2CH2-(4-morpholinyl); (15) -N(CH3)CH2CH2N(CH2CH2OCH3)2;
(16) -N(CH3)CH2CH2N(Et)2; (17) -N(CH3)CH2CH2CH2N(CH3)2; (18) -NHCH2CH(CH3)N(CH3)2; (19) -N(CH3)CH2CH2N(i-Pr)2; (20) -N(n-Pr)2; (21) -N(Et)2; (22) 3 chloraniline-; (23) 3-methoxyaniline-; (24) 4-foronline-; (25) -N(CH3)CH2CH2CH2CO2H; (26) -N(CH3)CH2CH2CH2C(O)NHSO2Ph; (27) -N(CH3)CH2CH2CH2)CH2Ph; (31) -NH-O-CH2Ph; (32) -N(CH3)(4-carboxyphenyl) or (33) -N(CH3)(4-benzensulfonamidelor).Or the compounds of formula
< / BR>in which A represents (1) -NHCH2CH2N(CH3)2; (2) -NH-CH2CO2H; (3) -N(CH3)CH2CH2N(CH3)2; (4) -N(Et)CH2CH2N(CH3)2; (5) -NHCH2CH2N(Et)2; (6) -NHCH2CH2-(4-morpholinyl); (7) -N(CH3)CH2CH2-(4-morpholinyl); (8) -N(CH3)CH2CH2N(CH2CH2OCH3)2; (9) -N(CH3)CH2CH2N(Et)2; (10) -N(Ph)CH2CH2N(CH3)2; (11) -N(CH3)CH2CH2CH2N(CH3)2; (12) -NHCH2CH2N(i-Pr)2; (13) -N(CH3)CH2CH2N(iPr)2; (14) -NHCH2CH2-(1-piperidinyl); (15) -N(CH3)CH2CH2-(1-piperidinyl); (16) -N(CH3)CH2CH2NHCH3; (17) -N(CH3)CH2CH2N(CH3)Ac; (18) -NHCH2CH2-(1-pyrrolidinyl); (19) -N(CH3)CH2CH2-(1-pyrrolidinyl); (20) -NHCH2CH2-(1H-1,2,4-triazole-4-yl); (21) -NH-CH2CH2-(1-imidazolyl); (22) -NH-CH2CH2-(2H-tetrazol-2-yl); (23) -NH-CH2CH2-(1H-tetrazol-1-yl); (24) -N(CH3)CH2CH2N(CH<>
< / BR>in which R represents (1) -CH3; (2) 4-forfinal; (3) 3-chlorophenyl; (4) phenyl; (5) benzyl; (6) hydrogen; (7) i-Pr; (8) i-Bu; (9) -CH2CO2Et; (10) -CH2CO2H; (11) Et; (12) Pr; (13) 2-pyrimidinyl; (14) -CH2CH2OC(O)NHCH3; (15) cyclopropyl or (16) -CH2CH2OH,
or compounds of the formula
< / BR>the values of n and A which are given in table. AND,
or compounds of the formula
< / BR>the values of n, R2and A which are given in table. B,
as well as the compounds of formula
< / BR>the values of n, R3and A IS
or formulas
< / BR>values of R2, R6and A which are given in table. D.In particular, preferred compounds are selected from
(a) Tert-butoxycarbonylmethyl(S-R*S*)]-4- ((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2 - azetidine)oxy)benzoate;
(b) 2-(bis)-(2-hydroxyethyl)amino)-2-oxoethyl (S-R*S*)]-4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2 - azetidine)oxy)benzoate;
(C) 1-methyl-2-oxo-2-(phenylmethoxy)ethyl (2S-(1(S*), 2R*, (R)))-4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoate;
(g) 1-carboxyethyl [S-(R*S*)] -4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoate;
(d) 2-(diethylamino)-1-methyl-2-oxoethyl [S-(R*S*)]-4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoate;
(e) [S-(R*S*)]-1-(((4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoyl)oxy)-acetyl)-L-Proline;
(W) [S-(R*S*)]-1-(((4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoyl)oxy)-acetyl-N-benzyl-L-prolinamide;
(C) 2-(dimethylamino)ethyl-[S-(R*S*)]-4-((the Il [S-(R*S*)]-4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)-benzoate;
(K) 3-dimethylamino-1-propyl [S-(R*S*)]-4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)-benzoate;
(l) 2-diethylaminoethyl [S-(R*S*)]-4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)-benzoate;
(m) 2-(1-(4-morpholino)ethyl)-[S-(R*S*)]-4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoate;
(h) 4-dimethylaminomethyl[S-(R*S*)]-4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoate;
(o) 2-dimethylamino-2-methyl-1-propyl[S-(R*S*)]-4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoate;
(p) 2-(diisopropylamino)ethyl[S-(R*S*)]-4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoate;
(b) benzyl[S-(R*S*)] -4-(2-((4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoyl)oxyethyl)-1-piperazine-carboxylate;
(C) 2-(dibutylamino)ethyl[S-(R*S*)]-4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoate;
(u) 2-(4-methyl-1-piperazinil)ethyl[S-(R*S*)]-4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoate;
(f) 2-(diphenylamino)ethyl[S-(R*S*)]-4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoate;
(x) 2-(di-2-propylamino)ethyl[S-(R*S*)]-4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoate;
(C) 2-(dimethylamino)-2-phenylethyl[S-(R*S*)]-4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoate;
(h) 2-(methyl(phenylmethyl)amino)ethyl[S-(R*S*)]-4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoate;
(W) 2-(dimethylamino)ethyl[S-(R*S*)]-4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)-2,6-dimethyl-benzoate;
(y) 2-(diethylamino)ethyl[S-(R*S*)]-4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)-2,6-dimethyl-benzoate;
(b) 2-(bis-(1-methylethyl)amino)ethyl[S-(R*S*)]-4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)-2,6-dimethyl-benzoate.Connection on p. 1, selected from the group including:
(a) [S-(Rseteditable;
(b) [S-(R*S*)] -2-(4-(((2-dimethylamino)ethyl)methylamino)-carbonyl)phenoxy)-3,3-diethyl-N-(1-(3,4-methylenedioxyphenyl)-butyl)-4-oxo-1-azetidinone;
(C) [S-(R*S*)]-2-(4-((4-methylpiperazin-1-yl) carbonyl)phenoxy)-3,3-diethyl-N-(1-(4-were)butyl)-4-oxo-1 - azetidinone;
(g) [S-(R*S*)]-2-(4-((4-methylpiperazin-1-yl) carbonyl)phenoxy)-3,3-diethyl-N-(1-(3,4-methylenedioxyphenyl)butyl)-4-oxo-1-azetidinone;
(d) [S-(R*S*)]-2-(4-((4-cyclopropylmethyl-1-yl)carbonyl)phenoxy)-3,3-diethyl-N-(1-(4-were)butyl)-4-oxo-1-azetidinone;
(e) [S-(R*S*)]-2-(4-((4-cyclopropylmethyl-1-yl)carbonyl)phenoxy)-3,3-diethyl-N-(1-(3,4-methylenedioxyphenyl)butyl)-4-oxo-1-azetidinone;
(W) [S-(R*S*)]-2-(4-((piperazine-1-yl)carbonyl)phenoxy)-3,3-diethyl-N-(1-(4-were)butyl)-4-oxo-1-azetidinone; or
(C) [S-(R*S*)]-2-(4-((piperazine-1-yl)carbonyl)phenoxy)-3,3-diethyl-N-(1-(3,4-methylenedioxyphenyl)butyl)-4-oxo-1-azetidinone;
(and) [S-(R*S*)]-2-(4-((((2-dimethylamino)ethyl)ethylamino)carbonyl)phenoxy)-3,3-diethyl-N-(1-(4-were) butyl)-4-oxo-1-azetidinone;
(K) [S-(R*S*)]-2-(4-((((2-diethylamino)ethyl)ethylamino)Carbo-hydroxyethyl)piperazine-1-yl)carbonyl)phenoxy)-3,3-diethyl-N-(1-(4-were)butyl)-4-oxo-1-azetidinone;
(m) [S-(R*S*)]-2-(4-(((4-(2-hydroxyethyl)piperazine-1-yl)carbonyl)phenoxy)-3,3-diethyl-N-(1-(3,4-methylenedioxyphenyl)butyl)-4-oxo-1-azetidinone; or
(n) [S-(R*S*)]-2-(4-(((4-ethoxycarbonylmethyl)piperazine-1-yl)carbonyl)phenoxy)-3,3-diethyl-N-(1-(3,4-methylenedioxyphenyl)butyl)-4-oxo-1-azetidinone;
Or connection, including:
(a) [S-(R*S*)]-2-(4-((4-morpholinyl)carbonyl)phenoxy)-3,3-diethyl-N-(1-(4-were)butyl)-4-oxo-1-azetidinone; or
(b) [S-(R*S*)]-2-(4-((4-morpholinyl)carbonyl)phenoxy)-3,3-diethyl-N-(1-(3,4-methylenedioxyphenyl)butyl)-4-oxo-1-azetidinone;
or represents:
(a) [S-(R*S*)]-2-(4-((((2-dimethylamino)ethyl)methylamino)carbonyl)phenoxy)-3,3-diethyl-N-(1-(4-were) butyl)-4-oxo-1-azetidinone;
(b) [S-(R*S*)]-2-(4-(((4-methyl)piperazine-1-yl)carbonyl)phenoxy)-3,3-diethyl-N-(1-(4-were)butyl)-4-oxo-1-azetidinone;
(C) [S-(R*S*)] -2-(4-(((4-methyl)piperazine-1-yl) carbonyl)phenoxy)-3,3-diethyl-N-(1-(3,4-methylenedioxyphenyl)butyl)-4-oxo-1-azetidinone;
(g) [S-(R*S*)]-2-(4-(((4-cyclopropyl)piperazine-1-yl)carbonyl)phenoxy)-3,3-diethyl-N-(1-(4-were)butyl)-4-oxo-1-a is-N-(1-(3,4-methylenedioxyphenyl)butyl)-4-oxo-1-azetidinone;
(e) [S-(R*S*)]-2-(4-((piperazine-1-yl)carbonyl)phenoxy)-3,3-diethyl-N-(1-(4-were)butyl)-4-oxo-1 - azetidinone; or
(W) [S-(R*S*)]-2-(4-((piperazine-1-yl)carbonyl) phenoxy)-3,3-diethyl-N-(1-(3,4-methylenedioxyphenyl)butyl)-4-oxo-1 - azetidinone;
connections, where
R represents a C1-3alkyl;
R1represents a C1-3alkyl;
M represents ethyl, propyl, butyl, pentyl or hexyl;
R2is:
(a) hydrogen;
(b) C1-6alkyl or C1-6alkoxy; or
R3represents hydrogen; or
R2and R3together with the formation of methylenedioxy;
each of R9, R10and R11chosen independently of one another from the group consisting of hydrogen, C1-4the alkyl and C1-3alkoxy-C1-3of alkyl;
R7and R8together with the nitrogen atom to which they are attached, form a mono - or di-substituted ring selected from the group including:
(1) piperidinyl; (2) piperazinil; (3) morpholinyl; (4) pyrrolidinyl; (5) peril; (6) imidazolyl; (7) triazolyl; (8) tetrazolyl; (9) pyrazolidine or (10) azetidinol,
each of the substituents selected from the group, Tyl, hydroxy-C1-3alkyl, C1-6alkoxy, C1-4allyloxycarbonyl and oxoprop.or connection, where
R represents methyl or ethyl;
R1represents methyl or ethyl;
M represents ethyl, propyl, butyl;
R2is:
(a) hydrogen; (b) C1-3alkyl or C1-3alkoxy.Especially compound a represents: [S-(R*S*)]-2-(4-((4-methylpiperazin-1-yl)carbonyl) phenoxy)-3,3-diethyl-N-(1-(3,4-methylenedioxyphenyl)butyl)-4-oxo-1-azetidinone or its pharmaceutically acceptable salt.All compounds exhibit activity of the elastase inhibitor of human leukocytes.Their invention also includes a pharmaceutical composition inhibiting the elastase of human leukocytes, comprising the active principle and a pharmaceutically acceptable carrier, characterized in that it contains as active principle an effective amount of a compound of any of the compounds of formula I.Preferred pharmaceutical composition containing as active ingredient a compound of formula I.The invention relates to a method of treating diseases caused by excessive activity of elastase by wedki effective amount of compound I.The invention is also a method of obtaining compounds of General formula I, in which
R represents ethyl,
R4mean group
< / BR>where Q, Y, R7and R8are specified in paragraph 1 values, which consists in the fact that the compound of General formula
< / BR>is treated with a compound having the formula:
< / BR>where R1, R1, R2, R3, R7, R8, Ra, Rb, M, Q and Y have the specified values.As was shown above when connecting R8, R9, R10and R12are formed of different rings. Below are non-limiting examples, showing how the form of rings are formed mainly at the connection of those or other substituents.R8and R9connect
< / BR>R9and R10connect
< / BR>R9and R12connect
< / BR>R10and R12connect
< / BR>R10and R12connect
< / BR>In another aspect the present invention relates to the treatment of leukemia, species such as alymphoplasia leukemia, acute myeloblastic leukemia (FAB FAB M1 and M2), acute promyelocytic leukemia (FAB M3), acute myelomonocytic leukemia (FAB M4), acute monocytic leukemia (FA leukemia and state, accompanying leukemia that involve activity PMA neutral proteases, in particular, disseminated intravascular coagulation, using compounds of formula I.Treatment of leukemic cells includes: introduction therapeutically effective amount of the compounds of formula I, which leads to inhibition of proteinase 3/myeloblastin, inhibition of elastase, the inhibition of proliferation of leukemia cells, induction of differentiation of leukemic cells and remission of the disease.In one alternative embodiment, the invention relates to a method of treating leukemia cells, which includes:
introduction to the patient in need of such treatment therapeutically effective amounts of compounds of formula I.In the second alternative embodiment, the invention relates to a method of inhibiting proteinase 3/myeloblastin, which includes:
introduction to the patient in need of such inhibition a therapeutically effective amount of compound I as defined above.In the third alternative embodiment, the invention relates to a method of inhibiting proteinase 3/myeloblastin and elastase, which includes:
introduction to the patient when necessary, the Eski acceptable salts thereof, as was defined above.In the fourth embodiment, the invention relates to a method of inducing cell differentiation of leukemic cells, which includes:
introduction to the patient in need of such inhibition a therapeutically effective amount of compound I or its pharmaceutically acceptable salt as defined above.Each of the above alternatives (i.e., related to the inhibition of PR3 or for cancer therapy) also refers to the joint introduction of the compounds of formula I, defined above, and the agent or agents traditionally used for the treatment of leukemia, including, but not limited to, Epsilon-aminocaproic acid, heparin, a drug (Aprotinin); prednisolone, cytosine arabinoside; beta-mercaptopurine; cytarabine; anthracyclin (see Young et al. (1981) N. Engl. J. Med. 305: 139), such as daunorubicin, doxorubicin and epidoxorubicin; derivatives of vitamin A, including retinoids and all TRANS-isomers of retinoic acid (see Ellison R. R. et al. (1968) Blood 32: 507. Arabinosyl cytosine: an agent used to treat leukemia in adult patients: Cytarabine: new therapeutic horizons. Semin. Oncol. 12: 1 (1985, Supp 3): Weinstein H. J. et al. (1983) Blood 62: 315. Chemotherapy of acute myeloblast the th alternative of the invention relates to pharmaceutical compositions, which includes:
the pharmaceutical carrier, a therapeutically effective amount of a compound selected from the group consisting of Epsilon-aminocaproic acid, heparin, drug, prednisolone, cytosine arabinoside, beta-mercaptopurine, tsitarabina, anthracycline and a derivative of vitamin A, as well as therapeutically effective amount of the compounds of formula I, as defined above.In the sixth alternative embodiment, the invention relates to a method of treating leukemia, which includes:
joint introduction to the patient in need of such treatment a therapeutically effective amount of a compound selected from the group consisting of Epsilon-aminocaproic acid, heparin, drug, prednisolone, cytosine arabinoside, beta-mercaptopurine, tsitarabina, anthracycline and a derivative of vitamin A; and therapeutically effective amounts of compounds of formula I, defined above.In the seventh alternative embodiment, the invention relates to a method of inhibiting proteinase 3/myeloblastin, which includes:
joint introduction to the patient in need of such inhibition a therapeutically effective amount of a compound selected IDA, beta-mercaptopurine, tsitarabina, anthracycline and a derivative of vitamin A, as well as therapeutically effective amount of the compounds of formula I, defined above.In the eighth alternative embodiment, the present invention relates to a method of inhibiting proteinase 3/myeloblastin, which includes:
introduction to the patient in need of such inhibition a therapeutically effective amount of a compound selected from the group consisting of Epsilon-aminocaproic acid, heparin, triazolyl, prednisolone, cytosine, arabinoside, beta-mercaptopurine, cytarabine, anthracyclin and a derivative of vitamin A, as well as therapeutically effective amount of the compounds of formula I, defined above.In the ninth alternative embodiment, the present invention relates to a method for induction in leukemic cells cell differentiation, which includes:
introduction to the patient in need of such induction therapeutically effective amount of a compound selected from the group comprising Epsilon-aminocaproic acid, heparin, triazolyl, prednisolone, cytosine arabinoside, beta-mercaptopurine, cytarabine, anthracyclin and a derivative of vitamin A, as well as tera is active variant of the invention represented compounds may be also used for the treatment of diseases, associated with overexpression of cDNA, such as, in particular, what are the diseases of the lungs, accompanied by abnormally viscous or sealed purulent secretions. Shown the presence of such compounds in the case of acute or chronic bronchopulmonary diseases, including infectious pneumonia, bronchitis or tracheobronchitis, bronchiectasis, cystic fibrosis, asthma, tuberculosis or fungal infections. The applicability of them are also useful in the case of atelectasis in connection with the development of lesions of the trachea or bronchi, and also as a result of complications after tracheostomy.In addition, the compounds of the present invention can be administered in conjunction with cDNA, which as shown earlier, has also found application in the case of lung diseases mentioned above, as reflected in document WO 90/07572.Compounds of the present invention are obtained by known methods or with the use of, among others, the synthesis schemes below for illustration. For example, methods for obtaining such compounds are described in patent EP 0337549, published on October 18, 1987, which is incorporated into this description by reference.The present invention relates also to a method of treatment of inflammatory variant of the coupling of the active component.It was shown that these compounds are able to function as effective inhibitors of the proteolytic activity of neutrophil elastase person, as demonstrated in tables 1 to 10.Determination of enzyme activity by inhibition of elastase from polymorphonuclear neutrophils person in the hydrolysis of N-t-BOC-alanyl-alanyl-propylalanine-p-nitroanilide (Side-AAPAN) or N-t-BOC-alanyl-proliferin-p-nitroanilide (Side-APWN) reagent:
0.05 M TES (N-Tris[hydroxymethyl]methyl-2-amino-econsultancy acid) buffer, pH 7.5.0.2 mm Side-AAPAN or Side-APWN.For the preparation of the substrate, the solid is first dissolved in 10.0 ml DMSO. After that add a buffer at pH 7.5 to a final volume of 100 ml.Crude extract containing the elastase from polymorphonuclear neutrophils (PMA) person.The investigated inhibitors (azetidinone) before using dissolved in DMSO.In the cell to 1.0 ml of 0.2 mm Side-AAPAN added 0.01-0.1 ml DMSO with or without inhibitor. After stirring conduct measurement at 410 MMK to detect products of spontaneous hydrolysis of the tested compounds. Then add 0.05 ml of extract PMA and spend ISM is
A. tert-Butoxycarbonylmethyl [S-(R*S*)]4-((3,3-di is>S*)] 4-((3,3-diethyl-1-(((1-(4-were)butyl)amino) carbonyl)-4-oxo-2-azetidine)oxy)benzoic acid about 3 ml of DMF added to 0.23 g of triethylamine, and then 0.50 g of tert-butylbromide and the resulting mixture was stirred over night at room temperature. Then add ethyl acetate (25 ml) and the resulting mixture is washed with water 2 to 10 ml, then 10 ml of saturated sodium bicarbonate solution and 20 ml of saline solution. The organic layer is dried over sodium sulfate and concentrated in vacuo. After chromatography on silica gel 60 (column 350 ml) and elution with 10% ethyl acetate in hexane get 0,67 g t-butoxycarbonylmethyl [S-(R*S*)]4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoate.Similarly can be prepared 2-(dimethylamino)-2-oxoethyl, (S-(R*S*))-4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoate (compound 6) and 2-(N-methylacetamide)ethyl, [2-(R*S*)] -4-(((3,3-diethyl-1-(((1-(4-methyl-phenyl) butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoate (compound 7).B. Carboxymethyl [2-(R*S*)] -4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoate
ice triperoxonane acid. The reaction mixture is stirred in the cold for three hours, then brought to room temperature. After 30 min the reaction mixture was concentrated in vacuo, and the residue chromatographic on silica gel 60. Elution with 20% ethyl acetate in hexane containing 1% acetic acid gives of 0.53 g of the desired carboxymethyl [S-(R*S*)]4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoate.Connection 2
Analytical data for C28H34N2O7+ 0,3 H2O
Calculation (in %): C - 65,19, H - 6.75 in, N - 5,43
Found: C - 65,30, H - 6,76, N - 5,23.Connection 6
Analytical data for C30H39N3O6+ 0,5 H2O
Calculation (in %): C - 65,91; H - 7,38; N - 7,60.Found: C - 65,71, H - 7,73, N - 7,50.Connection 7
Analytical data for C31H41N3O6+ 0,6 EtOAc
Calculation (in %): C - 66,35, H - of 7.64, N - 6,95.Found: C - 66,52, H - 7,89, N - 6,83.Example 2. 2-(bis(2-Hydroxyethyl)amino)-2-oxoethyl-(S-(R*S*))-4-((3,3-diethyl-1-(((4-(were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoate
To a solution of 0.125 g of acid form 1B in 2 to 3 ml of methylene chloride add 0,050 g carbonyldiimidazole. The mixture is stirred in the DMF and 2 ml of methylene chloride. The resulting mixture is stirred over night at room temperature, and then concentrated in vacuo. After chromatography of the residue on silica gel with elution from 2.5 to 5.0% methanol in methylene chloride receive 0,123 g of the desired compound 3 - 2-(bis(2-hydroxyethyl)amino)-2-oxoethyl (S-(R*S*))-4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoate.Connection 3
Analytical data for C32H43N3O8+ 0,4 H2O
Calculation (in %): C - 65,53, H - 7,30, N - 6,95.Found: C - 65,51, H - 7,45, N - 6,95.Connection 4
Analytical data for C31H40N4O7< / BR>Calculation (in %): C - 64,12, H - 6,94, N - 9,65.Found: C - 64,12, H - 7,18, N - 9,44.Connection 5
Analytical data for C32H43N3O9+ 0,3 H2O
Calculation (in %): C - 62,08, H - 7,09, N - 6,79.Found: C - 61,89, H - 7,39, N - 6,88.Compound 8
Analytical data for C40H47N3O8< / BR>Calculation (in %): C - 68,85, H - 6,79, N - 6,02.Found: C - 68,79, H - 7,06, N - 5,88.Example 3. Obtain 1-methyl-2-oxo-2-(phenylmethoxy)ethyl (2S-(1(S*), R*, -(R*)))-4-((3,3-diethyl-1-(((1-(4-were)b is SUP>*)] -4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoic acid in 10 ml of methylene chloride is added 2 ml of oxalicacid and then DMF) in an amount necessary for catalysis. The reaction mixture was stirred for 1 h at room temperature and then concentrated in vacuo to obtain the acid chloride, which is used in the next stage.B. a Solution of the above acid chloride in 10 ml of methylene chloride cooled in a water bath and add a solution of 1.25 g of benzyl-L-lactate and 2.0 g of triethylamine in 10 ml of methylene chloride. The mixture is stirred at room temperature overnight and then concentrated in vacuo. Chromatography of the residue on silica gel using methylene chloride as eluent gives 0,795 g of the desired 1-methyl-2-oxo-2-(phenylmethoxy)ethyl-(2S-(1(S*), R*, -(R)))-4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy) benzoate connection 10.Analytical data for C36H42N2O7< / BR>Calculation (in %): C - 70,34, H - 6,89, N - 4,56.Found: C - 70,45, H - 7,05, N - 4,48.Example 4. Getting 1-carboxyethyl [S-(R*S*)]-4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidinone hydrogen at a pressure of 40 pounds per inch2. After stopping the reaction the mixture is filtered and concentrated in vacuo to obtain 0.56 g of 1-carboxyethyl [S-(R*S*)]-4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoate connection 11.Analytical data for C29H36N2O7< / BR>Calculation (in %): C - 66,40, H - 6,92, N - 5,34.Found: C - 66,66, H - 7,26, N - Of 5.05.Example 5. 2-(Diethylamino)-1-methyl-2-oxoethyl-[S-(R*S*)]-4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoate.Acid (0,250 g) from example 4 is treated with oxalylamino by the method of example 3A, receiving the corresponding acid chloride. This material is dissolved in 5 of methylene chloride and add 0.4 ml of diethylamine. After 1 h the reaction mixture was concentrated in vacuo, and the residue is transferred into ethyl acetate and washed with saturated sodium bicarbonate solution. The organic phase is dried over sodium sulfate, concentrated and chromatographic the residue on silica gel. After elution with 5% ethyl acetate in methylene chloride receive the connection 12.Analytical data for C33H45N3O6< / BR>Calculation (in %): C - 68,37, H - of 7.82, N - 7,25.Found: C - 68,40, H - 7,93, N - 7,40.A. When a substitution in the procedure of example 3 of gasoline-L-lactate on hydrochloride benzyl ester of L-Proline receive the corresponding amide benzyl ester of L-Proline - connection 8.Analytical data for C40H47N3O8< / BR>Calculation (in %): C - 68,85, H - 6,79, N - 6,02.Found: C - 68,79, H - 7,06, N - 5,88.B. Recovery of the product obtained in example 6A in accordance with the procedure of example 4 gives compound 9.Analytical data for C33H41N3O8+ 0,5 H2O
Calculation (in %): C - 64,27, H - 6,86, N - for 6.81.Found: C - 64,49, H - 6,90, N - 6,68.Example 7. [S-(R*S*)]-1-(((4-((3,3-Diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoyl)oxy)acetyl-N-benzyl-L-prolinamide
Treatment of the acid obtained in example 6B, the connection 9 - in accordance with the procedure of example 3A gives the corresponding acid chloride, in the processing which benzylamino get the desired benzylated connection 19.Analytical data for C40H48N4O7< / BR>Calculation (in %): C - 68,95 H - 6,94, N - 8,04.Found: C - 68,93, H - 7,02, N - Of 7.96.Example 8. To a solution of acid chloride (obtained from 0.55 g of [S-(R*S*accordance with the procedure of example 3A), in 3 ml of methylene chloride add 0.15 g of N,N-dimethylaminoethanol. The reaction mixture was stirred at room temperature, concentrated in vacuo and then transferred to the ethyl acetate (25 ml) and washed with saturated sodium bicarbonate solution. The organic phase is dried over sodium sulfate and concentrated in vacuo. After chromatography on silica gel with elution with 2.5% methanol in methylene chloride receive 0,59 g of compound 1-2-(dimethylamino)ethyl(S-(R*S*))-4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoate.Analytical data for C30H41N3O5< / BR>Calculation (in %): C - 68,81, H - 7,89, N - 8,02.Found: C - 68,85, H - 8,09, N - 7,97.When replacing N,N-diethylaminoethylamine suitable aminoalcohols receive the corresponding esters.Connection 13
1-Dimethylamino-2-propyl [S-(R*S*)] -4-[[3,3-diethyl-1-[[[1- (4-were)butyl]amino]carbonyl]-4-oxo-2-azetidine]oxy] benzoate
Analytical data for C31H43N3O5< / BR>Calculation (in %): C - 69,25, H - 8,06, N - 7,82.Found: C - 68,97, H - 8,01, N - 7,80.The connection 14
3-Dimethylamino-1-propyl [S-(R*S*)]-4-[[3,3-diethyl-1-[[[1-(4-�43N3O5< / BR>Calculation (in %): C - 69,25, H - 8,06, N - 7,81.Found: C - 68,85, H - 8,19, N - 7,72.The connection 16
2-Diethylaminoethyl [S-(R*S*)] -4-[[3,3-diethyl-1-[[[1-(4-were)butyl]amino]carbonyl]-4-oxo-2-azetidine]oxy] benzoate
Analytical data for C32H45N3O6< / BR>Calculation (in %): C - 69,66, H is 8.22, N - 7,62.Found: C - 69,37, H - To 8.41, N - 7,51.Connection 17
2-(1-[4-Morpholino] ethyl [S-(R*S*)]-4-[[3,3-diethyl-1-[[[1-(4-were)butyl]amino]carbonyl]-4-oxo-2-azetidine]oxy] benzoate
Analytical data for C32H43N3O6< / BR>Calculation (in %): C - 67,94, H - 7,66, N - 7,43.Found: C - 67,67, H - Of 7.90, N - 7,26.The connection 18
4-Dimethylaminomethyl [S-(R*S*)] -4-[[3,3-diethyl-1-[[[1-(4-were)butyl]amino]carbonyl]-4-oxo-2-azetidine]oxy] benzoate
Analytical data for C32H45N3O5+ 0,2 H2O
Calculation (in %): C - 69,21, H - 8,24, N - 7,56.Found: C - 69,35, H - 8,24, N - 7,29.The connection 20
2-Dimethylamino-2-methyl-1-propyl-[S-(R*S*)]-4-[[3,3-diethyl-1-[[[1-(4-were)butyl]amino]carbonyl]-4-oxo-2-azetidine]oxy] benzoate
Analytical data for C32H45N32-(Diisopropylamino)ethyl-[S-(R*S*)] -4-[[3,3-diethyl-1-[[[1-(4-were)butyl]amino]carbonyl]-4-oxo-2-azetidine]oxy] benzoate
Analytical data for C34H49N3O5< / BR>Calculation (in %): C - 70,44, H - charged 8.52, N - 7,25.Found: C - 70,28, H - 8,76, N - 7,13.The connection 22
Benzyl-[S-(R*S*)] -4-[2-[[4-[[3,3-diethyl-1-[[[1-(4-were)butyl] amino] carbonyl] -4-oxo-2-azetidine]oxy]benzoyl]oxy]-ethyl]-1-piperazine-carboxylate
Analytical data for C40H50N4O7< / BR>Calculation (in %): C - 68.75 kilopascals, H - 7,21, N - 8,02.Found: C - 68,39, H - 7,30, N - 7,84.The connection 23
2-(Dibutylamino)ethyl [S-(R*S*)] -4-[[3,3-diethyl-1-[[[1-(4-were)butyl]amino]carbonyl]-4-oxo-2-azetidine]oxy] benzoate
Analytical data for C36H53N3O5< / BR>Calculation (in %): C - 71,14, H - 8,79, N - 6,91.Found: C - 71,00, H - 9,03, N - For 6.81.Connection 24
[S-(R*S*)] -6-(Dimethylamino)hexyl-4-[[3,3-diethyl-1-[[[1-(4-were)butyl]amino]carbonyl]-4-oxo-2-azetidine]oxy]-benzoate
Analytical data for C34H49N3O5+ 1H2O
Calculation (in %): C - 68,31, H at 8.60, N - 7,03.Found: C - 68,34, H - 8,29, N - 6,86.arbonyl]-4-oxo-2-azetidine]oxy]benzoate
Analytical data for C33H46N4O5+ 0,8 H2O
Calculation (in %): C - 66,82, H - 8,09, N - 9,44.Found: C - 67,28, H - 8,10, N - 8,96.The connection 28
2-(Diphenylamino)ethyl [S-(R*S*)] -4-[[3,3-diethyl-1-[[[1-(4-were)butyl]amino]carbonyl]-4-oxo-2-azetidine]oxy]benzoate
Analytical data for C40H45N3O5+ 1,4 H2O
Calculation (in %): C - 71,40, H - 7,16, N - 6,25.Found: C - 71,62, H - 6,99, N - 5,99.The connection 29
2-(di-2-Propylamino)ethyl [S-(R*S*)] -4-[[3,3-diethyl-1-[[[1-(4-were)butyl]amino]carbonyl]-4-oxo-2-azetidine]oxy]benzoate
Analytical data for C34H45N3O5< / BR>Calculation (in %): C - 70,93, H - 7,88, N - 7,30.Found: C - 71,18, H - 8,06, N - 7,34.The connection 30
2-(Dimethylamino)-2-phenylethyl [S-(R*S*)]-4-[[3,3-diethyl-1-[[[1-(4-were)butyl]amino]carbonyl]-4-oxo-2-azetidine]oxy]benzoate
Analytical data for C36H45N3O5< / BR>Calculation (in %): C - 72,09, H - 7,56, N - 7,00.Found: C - 71,75, H - To 7.67, N - 6,70.The connection 31
2-[Methyl(phenylmethyl)amino] ethyl [S-(R*S*)]-4-[[3,3-diethyl-1-[[[1-(4-were)butyl]amino]carbonyl]-4-oxo-2-azetidin the Nile] -4-oxo-2-azetidine] oxy]-2,6-dimethylbenzoic acid instead of [S-(R*S*)]-4-[[3,3-diethyl-1-[[[1-(4-were)butyl]amino] carbonyl]-4-oxo-2-azetidine]oxy] benzoic acid in the procedure of example 3A and the creation of conditions for the reaction of it with the corresponding aminoalcohols get the following esters.Connection 304
2-(Dimethylamino)ethyl [S-(R*S*)] -4-[[3,3-diethyl-1-[[[1-(4-were)butyl] amino]carbonyl]-4-oxo-2-azetidine]oxy]-2,6-dimethyl-benzoate
Connection 305
2-(Diethylamino)ethyl-[S-(R*S*)] -4-[[3,3-diethyl-1-[[[1-(4-were)butyl]amino]carbonyl]-4-oxo-2-azetidine]oxy]-2,6-dimethyl-benzoate
Connection 306
2-[bis(1-Methylethyl)amino] -ethyl [S-(R*S*)]-4-[[3,3-diethyl-1-[[[1-(4-were)butyl] amino] carbonyl] -4-oxo-2-azetidine] oxy]-2,6-dimethyl-benzoate
Treatment acid [S-(R*S*)] -4-[[3,3-diethyl-1-[[[1-(4-were)butyl] amino] carbonyl]-4-oxo-2-azetidine]oxy] benzooxazol acid oxalylamino in accordance with the procedure of example 3A leads to the corresponding acid chloride, which, after the reaction with the corresponding aminosterol by the method of example 8 gives the following amino esters:
The connection 32
Analytical data for C31H43N3O5< / BR>Calculation (in %):La C32H45N3O5< / BR>Calculation (in %): C - 69,66, H is 8.22, N - 7,62.Found: C - 69,10, H - 8,17, N - 7,50.The connection 34
Analytical data for C33H47N3O5< / BR>Calculation (in %): C - 70,06, H is 8.38, N - 7,43.Found: C - 69,70, H - To 8.41, N - 7,05.The connection 35
Analytical data for C33H45N3O6< / BR>Calculation (in %): C - 68,37, H - of 7.82, N - 7,25.Found: C - 68,55, H - 8,19, N - 7,08.The connection 36
Analytical data for C32H45N3O5< / BR>Calculation (in %): C - 69,66, H is 8.22, N - 7,62.Found: C - 69,60, H - 8,49, N - 7,55.Example 9. To a solution of 0,247 g of compound 1 in 2 ml of ethyl acetate added 0.125 g m-chloroperoxybenzoic acid. After 30 min standing at room temperature the reaction mixture was concentrated in vacuo. After chromatography of the residue on silica gel using for the elution of methylene chloride/methanol/water 85/15/1,5 receive the desired N-oxide compound 15.Analytical data for C30H41N3O8+ 1,4 H2O
Calculation (in %): C - 63,79, H - of 7.82, N - 7,44.Found: C - 63,89, H Is 7.85, N - 7,27.Example 10. [S-(R*S*)]-2-[4-[[[2-(Dimethylamino)-ethyl]amino]carbonyl]phenoxy]-3,3-diethyl-orida add a solution 0,227 g [S-(R*S*)]-4-((3,3-diethyl-1-((1-(4-were)butylamino)carbonyl)-4-oxo-2-azetidine)oxy) benzoic acid in 3 ml of methylene chloride. Within 30 min the mixture was stirred at ambient temperature, adding 0,100 g of N,N-dimethylethylenediamine. After stirring over night at room temperature the reaction mixture is poured into benzene (50 ml) and washed with water. The organic phase is separated, dried over sodium sulfate and concentrated in vacuo. After chromatography on silica gel followed by elution with 5% methanol in methylene chloride receive 0,160 g 2-[4-[[[2-(dimethylamino)ethyl]amino]carbonyl]phenoxy]-3,3-diethyl-N-[1-(4-were)butyl]-4-oxo-1-azetidinone.Connection 73
Analytical data for C30H42N4O4+ 0,4 H2O
Calculation (in %): C - 68,00, H - 8,14, N - 10,57.Found: C - 68,01, H - 8,18, N - To 10.62.Example 11.A. (S-(R*S*))-4-(3,3-Diethyl-1-((4-(were)butylamino)carbonyl)-4-oxo-2-azetidine)oxy)benzoyl chloride.To a solution 0,150 g [S-(R*S*)]-4-(3,3-Diethyl-1-(((1-(were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy) benzoic acid in 5 ml of methylene chloride containing dimethylformamide in number, neophobia and then concentrated in vacuo to obtain (S-(R*S*))-4-((3,3-diethyl-1-((1-(4-were)butylamino)carbonyl)-4-oxo-2-azetidine)oxy)benzoyl chloride.B. [S-(R*S*)]-2-[4-[[[2-(dimethylamino)-ethyl]methylamino]-carbonyl]-phenoxy-3,3-diethyl-N-[1-(4-were]butyl]-4-oxo-1-azetidinone.The above acid chloride dissolved in 3 ml of methylene chloride and add a solution of 0.20 g of N,N,N'-trimethylethylenediamine in 2 ml of methylene chloride. The mixture is stirred overnight and then concentrated in vacuo. The residue is extracted by distributing between phases ethyl acetate and saturated sodium bicarbonate solution. The organic phase is dried over sodium sulfate and concentrated in vacuo. Chromatography of the residue on silica gel (5% methanol in methylene chloride) gives 0,117 g [S-(R*S*)]-2-[4-[[[2-(dimethylamino)ethyl]methylamino] carbonyl] phenoxy-3,3-diethyl-N-[1-(4-were] butyl]-4-oxo-1-azetidinone.Connection 75
Analytical data for C31H44N4O4+ 0,5 H2O
Calculation (in %): C - 68,23, H - 8,31, N - 10,27.Found: C - 68,20, H - To 8.41, N - 10,10.When replacing N, N,N'-trimethylethylenediamine in example 11B to the desired amines obtain the corresponding amides.1) Connection 76
Analytical 8,60, N - 9,54.2) Connection 77
Analytical data for C32H46N4O4+ 0,75 H2O
Calculation (in %): C - 68,12, H - 8,49, N - to 9.93.Found: C - 68,22, H - 8,48, N - 10,17.3) Connection 78
Analytical data for C32H44N4O5< / BR>Calculation (in %): C - 68,06, H is 7.85, N - 9,92.Found: C - 67,84, H - 8,07, N - 9,62.4) Connection 79
Analytical data for C33H46N4O5+ H2O
Calculation (in %): C - 66,42, H - 8,11, N - 9,39.Found: C - 66,73, H - 8,19, N - 9,23.5) Connection 80
Analytical data for C35H52N4O6< / BR>Calculation (in %): C - 67,28, H - 8,39, N - 8,97.Found: C - 67,08, H - 8,77, N - To 8.41.6) Connection 81
Analytical data for C33H48N4O4+ H2O
Calculation (in %): C - 68,01, H - 8,65, N being 9.61.Found: C - 68,42, H - 8,59, N - 9,17.7) Connection 82
Analytical data for C36H46N4O4+ 0,5 H2O
Calculation (in %): C - 71,14, H - 7,79, N - of 9.21.Found: C - 71,41, H - 7,68, N - 9,10.8) Connection 83
Analytical data for C32H46N4O4+ 1,2 H2O
Calculation (in %): C - 67,15, H - charged 8.52, N - 9,79.Found>2N4O4< / BR>Calculation (in %): C - 70,91, H - 8,84, N - 9,45.Found: C - 70,37, H - 8,84, N - 8,77.11) Connection 89
Analytical data for C31H39N5O4+ 0,7 H2O
Calculation (in %): C - 66,71, H - 7,29, N - 12,54.Found: C - 66,91, H - 7,40, N - 12,14.12) Connection 90
Analytical data for C33H46N4O4+ 0,8 H2O
Calculation (in %): C - 68,67, H - 8,31, N - 9,70.Found: C - 68,82, H - 8,11, N - 9,70.13) Connection 91
Analytical data for C34H48N4O4+ 0,3 H2O
Calculation (in %): C - 70,11, H - to 8.41, N being 9.61.Found: C - 70,17, H - 8,64, N Was 9.33.14) the Compound 92
Analytical data for C30H42N4O4+ 1,2 H2O
Calculation (in %): C - 66,14, H is 8.22, N - 10,92.Found: C - 66,18, H - 8,12, N - 10,31.15) Connection 93
Analytical data for C32H44N4O6+ 0,3 H2O
Calculation (in %): C - 65,57, H - to 7.67, N - 9,56.Found: C - 65,72, H - 7,50, N - 9,34.16) Connection 94
Analytical data for C32H44N4O4+ 0,3 H2O
Calculation (in %): C - 70,04, H - 8,08, N - of 10.21.Found: C - 70,34, H - 8,90, N - 8,93.17) the Connection 95
Ana is x2">Found: C - 69,41, H - 8,25, N - 9,58.18) Connection 99
Analytical data for C38H54N4O4+ 1,5 H2O
Calculation (in %): C - 69,37, H - 8,72, N - 8,51.Found: C - 69,48, H - 8,44, N - At 8.36.19) Connection 102
Analytical data for C40H49N5O6+ 1,0 H2O
Calculation (in %): C - 67,30, H - 7,20, N - 9,81.Found: C - 67,50, H - 7,24, N - At 9.53.20) Connection 104
Analytical data for C32H41N5O4+ 0,75 H2O
Calculation (in %): C - 67,04, H - 7,47, N - 12,21.Found: C - 67,16, H - 7,56, N - 11,95.21) Connection 105
Analytical data for C32H44N4O5+ 0,5 H2O
Calculation (in %): C - 66,99, H - to $ 7.91, N - 9,77.Found: C - 67,00, H - 8,25, N - 9,50.22) Connection 106
Analytical data for C32H45N5O5+ 0,8 H2O
Calculation (in %): C - 64,69, H - of 7.90, N - 11,78.Found: C - 64,93, H - 8,25, N - 11,12.23) Connection 107
Analytical data for C31H44N3O6S + 0,3 H2O
Calculation (in %): C - 61,42, H - 7,41, N - 9,24.Found: C - 61,43, H - 7,54, N - 9,05.24) Connection 110
Analytical data for C35H44N4O4< / BR>34H42N4O4+ 0,5 H2O
Calculation (in %): C - 70,44, H - 7,47, N - 9,66.Found: C - 70,82, H - 7,46, N - 9,20.26) Connection 113
Analytical data for C34H42N4O4+ 0,3 H2O
Calculation (in %): C - to $ 70.88, H - 7,45, N - 9,72.Found: C - 71,12, H - 7,44, N - To 9.32.27) 115 Connection
Analytical data for C34H42N4O4+ 0,7 H2O
Calculation (in %): C - 69,99, H - 7,50, N - 9,60.Found: C - 70,14, H - 7,63, N - 9,25.28) Connection 116
Analytical data for C34H46N4O4+ 1,4 H2O
Calculation (in %): C - 68,06, H - 8,19, N was 9.33.Found: C - 68,40, H - 8,14, N - 8,87.29) Connection 117
Analytical data for C40H51N5O6+ 0,6 H2O
Calculation (in %): C - 67,79, H - 7,42, N - 9,88.Found: C - 67,81, H - 7,58, N - 9,76.30) Connection 118
Analytical data for C33H47N5O4+ 0,7 H2O
Calculation (in %): C - 67,14, H compared to 8.26, N - up 11,86.Found: C - 67,54, H - 8,51, N - 11,28.31) Connection 119
Analytical data for C35H48N4O4+ 1,25 H2O
Calculation (in %): C - 68,76, H - 8,32, N - 9,16.Found: C - 69,07, H - 8,19, N - 8,75.32C - 68,66, H - OF 8.47, N - 9,42.Found: C - 69,02, H - 8,32, N - 9,06.33) Connection 125
Analytical data for C37H48N4O4+ 0,5 H2O
Calculation (in %): C - 71,47, H - 7,94, N - 9,01.Found: C - 71,65, H - To $ 7.91, N - 8,73.34) Connection 126
Analytical data for C41H54N4O5+ 2H2O
Calculation (in %): C - 68,83, H - 8,25, N - of 7.64.Found: C - 69,03, H - 7,79, N - 7,50.35) Connection 132
Analytical data for C35H50N4O4< / BR>Calculation (in %): C - 71,15, H - 8,53, N - 9,48.Found: C - 70,90, H - A Total Of 8.74, N - 9,12.36) Connection 133
Analytical data for C40H52N4O4+ 0,9 H2O
Calculation (in %): C - 71,80, H - 8,10, N - of 8.37.Found: C - 71,86, H - 8,17, N - 8,18.37) Connection 137
Analytical data for C37H48N4O4+ 0,8 H2O
Calculation (in %): C - 70,85, H - 7,97, N - 8,93.Found: C - 71,01, H - 7,97, N - 8,54.38) Connection 139
Analytical data for C39H51N5O4+ 0,8 H2O
Calculation (in %): C - 70,09, H - 7,93, N - 10,48.Found: C - 70,18, H - 7,79, N - 10,42.39) Connection 142
Analytical data for C38H55N5O634H51N5O4< / BR>Calculation (in %): C - 68,77, H - 8,66, N - 11,80.Found: C - 68,57, H - 8,50, N - 11,53.41) Connection 144
Analytical data for C38H59N5O4+ 0,4 H2O
Calculation (in %): C - 69,45, H - 9,17, N - 10,65.Found: C - 69,69, H - 9,02, N - 10,35.42) Connection 145
Analytical data for C36H47N5O4+ H2O
Calculation (in %): C - 68,44, H - of 7.82, N - 11,08.Found: C 68,69, H - 7,74, N - 10,76.43) Connection 148
Analytical data for C36H47N5O4+ 0,4 H2O
Calculation (in %): C - 69,62, H - 7,56, N - 11,27.Found: C - 69,79, H - 7,70, N - 11,12.44) Connection 149
Analytical data for C39H50N4O4+ 0,4 H2O
Calculation (in %): C - 72,50, H - 7,93, N - 8,67.Found: C - 72,44, H - 7,99, N - 8,87.45) Connection 150
Analytical data for C36H47N5O4+ 0,3 H2O
Calculation (in %): C - 69,83, H - 7,74, N - 11,31.Found: C - 69,93, H - 7,65, N - 11,10.46) Connection 151
Analytical data for C33H47N5O4< / BR>Calculation (in %): C - 68,60, H - 8,20, N - 12,12.Found: C - 68,40, H - 8,16, N - 11,90.47) Connection 245
And the network: C - 72,49, H - 7,49, N - 9,25.48) Connection 246
Analytical data for C37H46N4O4+ 0,25 H2O
Calculation (in %): C - 72,26, H - to 7.61, N - 9,10.Found: C - 72,35, H - 7,83, N - 8,73.49) Connection 154
Analytical data for C35H48N4O4+ 0,8 H2O
Calculation (in %): C - 69,70, H - 8,29, N - 9,29.Found: C - 69,65, H - 8,27, N - 9,35.50) Connection 158
Analytical data for C35H48N4O4+ 0,5 H2O
Calculation (in %): C - 73,29, H - 7,65, N - 8,33.Found: C - 73,71, H To 7.75, N - 7,75.51) Connection 159
Analytical data for C35H48N4O4< / BR>Calculation (in %): C - 73,09, H - 7,66, N - 8,31.Found: C - 73,40, H To 7.75, N - 7,80.52) Connection 160
Analytical data for C38H48N4O4+ 1,0 H2O
Calculation (in %): C - 70,78, H - 8,12, N - 8,68.Found: C - 71,00, H - 8,05, N - 8,59.53) Connection 161
Analytical data for C43H52N4O4+ 1 H2O
Calculation (in %): C - 73,05, H - 7,70, N - 7,92.Found: C - 73,29, H - 7,95, N - 7,37.54) Connection 166
Analytical data for C33H46N4O4+ 1,5 H2O
Calculation (in %): C - 67.2 per C36H52N4O6+ 1,6 H2O
Calculation (in %): C - 64,95, H - at 8.36, N - to 8.41.Found: C - 65,26, H - 8,15, N - 8,07.56) Connection 177
Analytical data for C38H47N5O4< / BR>Calculation (in %): C - 71,56, H - 7,43, N - 10,98.Found: C - 71,64, H - 7,62, N - Of 10.93.57) 178 Connection
Analytical data for C38H50N4O4< / BR>Calculation (in %): C - 72,81, H - 8,04, N - 8,94.Found: C - 72,96, H - 8,17, N - 8,83.58) Connection 179
Analytical data for C38H47N5O4< / BR>Calculation (in %): C - 71,56, H - 7,43, N - 10,98.Found: C - 72,00, H - At 7.55, N - 10,87.59) Connection 180
Analytical data for C38H47F3N4O4< / BR>Calculation (in %): C - 67,04, H - of 6.96, N - 8,23.Found: C - 67,02, H - 7,25, N - 8,23.60) Connection 181
Analytical data for C38H47F3N4O4< / BR>Calculation (in %): C - 67,04, H - of 6.96, N - 8,23.Found: C - 66,63, H - 6,98, N - 7,94.61) Connection 182
Analytical data for C37H47FN4O4< / BR>Calculation (in %): C - 70,45, H - 7,51, N - 8,88.Found: C - 70,28, H - 7,74, N - 8,82.62) 185 Connection
Analytical data for C34HAnalytical data for C37H48N4O4+0,8 H2O
Calculation (in %): C - 70,85, H - 7,97, N - 8,93.Found: C - 71,12, H - 8,25, N - 8,45.64) Connection 191
Analytical data for C42H51N5O4+ 0,5 CH2Cl2< / BR>Calculation (in %): C - 69,78, H - 7,16, N - 9,58.Found: C - 69,75, H - 7,31, N - 9,68.65) Connection 203
Analytical data for C37H47N4O4+ 1,1 H2O
Calculation (in %): C - 68,31, H - 7,62, N - 8,61.Found: C - 68,32, H - EUR 7.57, N - 8,53.66) Connection 204
Analytical data for C37H47ClN4O4< / BR>Calculation (in %): C - 68,66, H - 7,32, N - 8,66.Found: C - 68,32, H - Of 7.48, N - 8,42.67) Connection 205
Analytical data for C38H50N4O5+ 0,7 H2O
Calculation (in %): C - 69,63, H - of 7.90, N - 8,54.Found: C - 69,72, H - To $ 7.91, N - 8,54.68) Connection 206
Analytical data for C39H52N4O6+ 0,8 H2O
Calculation (in %): C - 68,15, H - 7,86, N - 8,15.Found: C - 68,01, H - 8,02, N - 8,15.Example 12.A) [S-(R*S*)] -3,3-Diethyl-2-[4-[[[2-(4-hydroxy-1-piperidinyl)ethyl] amino] carbonyl] phenoxy]-N-[1-(4-were)butyl]-4-oxo-1-assetid who receive [S-(R*S*)]-3,3-diethyl-2-[4-[[[2-(4-benzyloxy-1 - piperidinyl] ethyl] amino] carbonyl] phenoxy]-N-[1-[4-were)butyl]-4-oxo-1-azetidinone.B) [S-(R*S*)] -3,3-Diethyl-2-[4-[[[2-(4-hydroxy-1 - piperidinyl)ethyl] amino] carbonyl] phenoxy]-N-[1-(4-were)butyl]-4-oxo-1-azetidinone
A solution of the amide obtained above in stage A, in 10 ml of glacial acetic acid containing 22 mg of 10% Pd/C, hydrogenizing in an atmosphere of hydrogen under a pressure of 42 pounds. When TLC is determined by the completion of the reaction, the mixture is filtered and concentrated in vacuo after addition of 50 ml of toluene. The residue is dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic phase is dried over sodium sulfate and concentrated in vacuo. The remainder chromatographic using silica gel (15 g), elution with 5% methanol in methylene chloride gives 96 mg of [S-(R*S*)]-3,3-Diethyl-2-[4-[[[2-(4-hydroxy-1 - piperidinyl)ethyl] amino] carbonyl]phenoxy]-N-[1-(4-were)butyl]-4-oxo-1-azetidinone.Analytical data for C33H46N4O5+ 1,3 H2O
Calculation (in %): C - 65,83, H - 8,13, N - OF 9.30
Found: C - 66,10, H - 8,06, N - 8,91
When substituting in the procedure of example 12 1-(2-amino-ethyl)BR> 1) Connection 129
Analytical data for C34H48N4O5< / BR>Calculation (in %): C - 68,89, H - 8,16, N - 9,45.Found: C - 68,68, H - 8,18, N - 8,65.2) Connection 131
Analytical data for C32H44N4O5+ 1H2O
Calculation (in %): C - 65,92, H - of 7.96, N being 9.61.Found: C - 66,07, H - 7,86, N - 9,45.3) Connection 138
Analytical data for C33H46N4O5+ 0,5 H2O
Calculation (in %): C - 67,43, H - 8,06, N - at 9.53.Found: C - 67,61, H - 8,06, N - 9,37.Diamino intermediates
Described in the present invention, the diamines used to obtain aminoamides, commercially available when performing the following procedure:
< / BR>Example 13.A. Cyanomethylphosphonate
To a solution of 1.98 g homopiperazine in 50 ml of acetone type of 4.25 g of powdered anhydrous sodium carbonate and 1.3 ml of chloroacetonitrile. After 24 h the reaction mixture was filtered and washed with filtered cake in 100 ml of acetone. The combined filtrates concentrated in vacuo, and the residue chromatographic on silica gel using for the elution of methylene chloride. Output N-cyanomethylphosphonate is 2,69,B. N-(2-amino-ethyl)somethingimportant in 25 ml of ether. After adding the full set of components in the mixture is heated to boiling point under reflux for 1 h, then cooled to room temperature and gently stop the reaction by adding successively 1 ml water, 1 ml of 15% sodium hydroxide solution and 3 ml of water. The mixture is filtered through sodium sulfate, filtered, the cake washed thoroughly with ether, and the combined filtrates concentrated in vacuo to obtain 2,60 g of N-(2-amino-ethyl)homopiperazine.< / BR>Example 14. N-(2-amino-ethyl)homopiperazin.A) N-(2-formimidoyl)homopiperazin.To a carefully prepared solution 0,718 g of 60% dispersion of sodium hydride in 75 ml of absolute ethanol, cooled to 0oC add 7.3 ml ethyl ester of formic acid. After 5 minutes the mixture was added a solution of 2.55 g of N-(2-amino-ethyl)homopiperazine in 25 ml of absolute ethanol. During the night the mixture was stirred at room temperature. After that add a saturated solution of sodium bicarbonate (15 ml), then stirred the mixture with 150 ml of ethyl acetate, filtered through MgSO4and the filtrate concentrated in vacuo. After chromatography of the residue on silica gel (150 g) using for the elution of methylene chloride/methanolic)homopiperazin
To a solution of 2.75 g of N-(2-formimidoyl)homopiperazine in 20 ml of dry THF in an atmosphere of N carefully add 60 ml boranova the THF solution. After the addition was finished the reaction mixture is heated at the boiling point under reflux for 5 h and then stirred at room temperature overnight. The reaction is stopped by the cautious addition of 20 ml of 6N HCl and then boil the mixture under reflux for 1 h then the reaction mixture is cool, add 50 ml of water and using solid KOH gently bring the pH to alkaline values. After extraction with ether to obtain the desired product N-(2-methylamino)homopiperazin.Example 15.< / BR>A) N-benzyl-N,N'-dimethyl-N'-(2-phenylethyl)Ethylenediamine
The mixture to 0.900 g of N-benzyl-N,N'-dimethylethylenediamine, 1.10 g of powdered sodium carbonate and 0.75 ml of 2-phenylethylamine refluxed for 5 hours while boiling add an additional 0.25 ml of the bromide. Then the reaction mixture is cooled and filtered. The filtrate was concentrated in vacuo and chromatographic on silica gel with elution CH2Cl2/CH3OH/NH4OH (97/3/0,3) obtaining 0,875 g of N-benzyl-N,N'-dimethyl-N'-(2-phenylethyl)e is-phenylethyl)Ethylenediamine in 10 ml ethanol and 5 ml acetic acid is added 0.18 g of Pd(OH)2/C. the Mixture hydrogenizing at a pressure of 40 pounds/inch2for 3.5 h, then filtered and concentrated in vacuo. The residue is alkalinized with 1N NaOH and the extraction is carried out with ethyl acetate (5 25 ml). The combined extracts filtered through sodium sulfate and concentrated to obtain N, N'-dimethyl-N-(2-phenylethyl)Ethylenediamine.Example 16.< / BR>A solution of 1.28 g of 1-(2-amino-ethyl)piperidine and 1.07 g of pyridine-3-carboxaldehyde in 40 ml of toluene is heated at the boiling point under reflux using Dean stark trap (Dean Stark). In the analysis of 10 ml of distilled toluene by NMR showed the absence of the specified aldehyde. Then the reaction mixture was concentrated, and the resulting Imin used directly in the next stage.B) To a suspension 0,380 g of lithium hydride-aluminum in 30 ml of dry THF which was cooled to -10oC, is added dropwise a solution of the above imine in 20 ml of dry THF. After about 1 h the cooled reaction mixture is stopped by adding 5 ml of 5N NaOH, then this mixture is diluted with 100 ml of ether and 20 ml of water. The organic phase is separated, washed with brine, filtered through sodium sulfate and concentrated to obtain 2.17 g of 1-[2-(3-BR>To 7.50 g of N, N'-dimethylethylenediamine, cooled in a bath containing ice-ethanol, add portions over a 30 minute period of 1.40 g of 3-picolylamine. After complete addition, the reaction mixture is stirred in the cold for 1 h, concentrated in vacuo, and the resulting residue partitioned between phases 50 ml of ether and 10 ml of 5N NaOH solution. The organic layer is separated and the aqueous layers are extracted twice with 50 ml of ether. The combined organic phases are dried over sodium sulfate and concentrated in vacuo. Chromatography on 150 ml of silica gel using CH2Cl2/CH3OH/NH4OH 90/10/1) as eluent gives 0.930 g N,N'-dimethyl-N-(3-pyridylmethyl)Ethylenediamine.Example 18. Amino acid ---> diamine.A) To a cooled on ice to a solution to 2.29 g of N-CBZ-D-Proline in 50 ml of CHCl2added 1.35 g of 1-hydroxybenzotriazole and then to 2.06 g dicyclohexylcarbodiimide. After 20 minutes add 0,85 ml pyrrolidine and the reaction mixture is stirred overnight, after which it is filtered, and the filtrate was concentrated in vacuo. The residue is distributed between the phases 100 ml of ethyl acetate and 50 ml of 2N hydrochloric acid. The organic phase is separated, washed with 50 ml of 1.0 sodium hydroxide solution, vegatest eluent ethyl acetate in hexane different concentrations (30-100%) gives 2,04 g of the desired amide of pyrrolidine.B) To a solution of 1,519 g amide (obtained in paragraph (A) in 20 ml of absolute ethanol is added 75 mg of catalyst in the form of 10% Pd on carbon. The mixture hydrogenizing at a pressure of 40 pounds/inch2approximately one hour and then filtered, and the filtrate concentrated to obtain the amide of D-polypyrrolidone.C) To a suspension 0,380 g of lithium hydride-aluminum in 15 ml of dry tetrahydrofuran carefully add a solution of the amide of D-Proline (obtained above in paragraph (B) in 10 ml of tetrahydrofuran. The mixture is refluxed for 2 hours, then cooled and stop the reaction by adding 2 ml of 2.5 N sodium hydroxide. The mixture is filtered through a pad with sodium sulfate, and the obtained filtered cake was washed with 2 50 ml of ether. The combined filtrates concentrated in vacuo to obtain the 0.80 g of the desired 2-(1-pyrrolidinyl)pyrrolidine.Example 19. [S-(R*S*)]-2-[4-[[(4-Methyl)piperazine-1-yl]carbonyl]phenoxy]-((3,3-diethyl-N-[1-(were/butyl]-4-oxo-1 - azetidinone.A solution of [S-(R*S*)] -4-(((3,3-diethyl-1-((4-were)-butylamino)carbonyl)4-oxo-2-azetidine)oxy) benzoyl chloride (3.8 mmol) obtained by the procedure of example 11A, in 50 ml of methylene chloride cooled in an ice bath and mesilat for 1 h and then poured into a mixture of ice water and 10% potassium carbonate. The product is extracted with two portions of methylene chloride, washing each layer of methylene chloride portion of the salt solution. Layers in methylene chloride combine, dried over sodium sulfate and evaporated. The residue is subjected to a cleaning method of a flash chromatography using elution initially ethyl acetate, then 2% triethylamine/10% methanol/88% ethyl acetate to obtain 2.1 g of the target compound as a white solid.Analytical data for C30H42N4O4< / BR>Calculation (in %): C - 69,64, H - 7,92, N - 10,48.Found: C - 69,62, H - 8,23, N - 10,46.Example 20. [S-(R*S*)]-2-[4-[[(4-Methyl)piperazine-1-yl]carbonyl]phenoxy] -((3,3-diethyl-N-[1-(3,4-methylenedioxyphenyl)butyl] -4-oxo-1-azetidinone
During the reaction of [S-(R*S*)]-4-((((3,3-diethyl-1-(3,4-methylenedioxyphenyl)butylamino)carbonyl)-4-oxo-2-azetidine)oxy) benzoyl chloride (3.1 mmol) obtained by the method of example 11A N-methylpiperazine according to the method as described in example 19, the gain of 1.75 g of the target compound.Analytical data for C31H40N4O6< / BR>Calculation (in %): C - 65,94, H - 7,14, N - 9,92.Found: C - 65,80, H - 7,31, N Of 10.05.Example 21. [S-(R*S*)]-2-[4-[[(4-Hydroxy the reaction, [S-(R*S*)]-4-(((3,3-diethyl-1-((4-(were)butylamino)carbonyl)-4-oxo-2-azetidine)oxy) benzoyl chloride (3.8 mmol) obtained by the method of example 11 from N-(2-hydroxyethyl)piperazine (7.6 mmol) and diisopropylethylamine (3.8 mmol) by the method as described in example 19, to obtain 2.1 g of the target compound.Analytical data for C32H44N4O5< / BR>Calculation (in %): C - 68,06, H is 7.85, N - 9,92.Found: C - 67,88, H - 7,87, N - 10,17.Example 22. [S-(R*S*)]-2-[4-[[(4-Hydroxyethyl)piperazine-1-yl]carbonyl] phenoxy] -((3,3-diethyl-N-[1-(3,4-methylenedioxyphenyl)butyl] -4-oxo-1-azetidinone
During the reaction of [S-(R*S*)]-4-(((3,3-diethyl-1-((3,4-methylenedioxyphenyl)butylamino)carbonyl)-4-oxo-2-azetidine)oxy) benzoyl chloride (3.1 mmol) obtained by the method of example 11 from N-(2-hydroxyethyl)piperazine (6.2 mmol) and diisopropylethylamine (3.1 mmol) by the method as described in example 19, to obtain 1.50 g of the target compound.Analytical data for C32H42N4O71,5 H2O
Calculation (in %): C - 61,94, H - 6,89, N - 9,06.Found: C Of 61.95, H - 6,92, N - 8,96.Example 23. [S-(R*S*)]-2-[4-[[(4-Cyclopropyl)piperazine-1-yl]carbonyl] phenoxy]-((3,3-diethyl-N-[1-(4-were) is about)carbonyl)-4-oxo-2-azetidine)oxy) benzoyl chloride (3.8 mmol), obtained by the procedure of example 11A, in 50 ml of methylene chloride added N-(cyclopropyl)piperazineethanol (5.7 mmol) and then within a 5-minute period while cooling in an ice bath, make a solution of diisopropylethylamine (15.8 mmol) in 10 ml of methylene chloride. The reaction mixture was stirred for 1 h at 0oC, after which it was poured into ice water. The product is extracted with two portions of methylene chloride, with each portion was washed with brine. Phase with methylene chloride combine, dried over sodium sulfate, and then chromatography using ethyl acetate/50% hexane and then 70% ethyl acetate/30% hexane gives 2.1 g of the target compound as a white solid.Analytical data for C32H42N4O4< / BR>Calculation (in %): C - 70,69, H - to $ 7.91, N - 9,99.Found: C - 70.62 Per, H - 8,04, N - 9,95.Example 24. [S-(R*S*)]-2-[4-[[4-Cyclopropyl/piperazine-1-yl]carbonyl] phenoxy] -(3,3-diethyl-N-[1-(3,4 - methylenedioxyphenyl)butyl] -4-oxo-1-azetidinone
During the reaction of [S-(R*S*)]-4-(((3,3-diethyl-1-((3,4-methylenedioxyphenyl)butylamino)carbonyl)-4-oxo-2-azetidine)oxy) benzoyl chloride (3.1 mmol) obtained by the method of example 11 from N-(cyclopropyl)piperazin the ptx2">Analytical data for C32H42N4O7< / BR>Calculation (in %): C - 67,10, H - 7,17, N - 9,49.Found: C - 67,03, H - 7,31, N For 9.47.Example 25. [S-(R*S*)] -2-[4-[[4- Piperazine-1-yl]carbonyl]phenoxy]-3,3-diethyl-N-[1-(4-were)butyl]-4-oxo-1-azetidinone
Stage A:
[S-(R*S*)] -2-[4-[[4-(t-butoxycarbonyl) piperazine-1-yl]carbonyl]phenoxy]-((3,3-diethyl-N-[1-(4-were)butyl]-4-oxo-azetidinone
[S-(R*S*)]-4-(((3,3-Diethyl-1-((4-(were)butylamino)-carbonyl)-4-oxo-2-azetidine)oxy)benzoyl chloride (0.4 mmol) obtained in example 11A, is reacted with N-(t-butoxycarbonyl)piperazine (0.6 mmol) and triethylamine (1.2 mmol) as described in example 23. Thus obtained coarse target product is directly used further in the next stage B.Stage B:
[S-(R*S*)]-2-[4-[Piperazine-1-yl]carbonyl]phenoxy]-((3,3-diethyl-N-[1-(4-were)butyl]-4-oxo-1-azetidinone
The product obtained at stage A, dissolved in 0.5 ml of anisole, and then add 2 ml of cold TFU. The reaction mixture was stirred at 0oC for 1 h, then diluted with methylene chloride and evaporated. The residue is transferred in methylene chloride, washed with the clear method flash chromatography using first 5%, then 10% methanol/methylene chloride, resulting in a gain 0,212 g of the target product.Analytical data for C30H40N4O51H2O
Calculation (in %): C - 66,89, H is 7.85, N - the 10.40.Found: C - 67,06, H - At 7.55, N - 10.30 A.m.Example 26. [S-(R*S*)]-2-[4-[[(4- Piperazine-1-yl]carbonyl]phenoxy]-((3,3-diethyl-N-[1-(3,4-methylenedioxyphenyl)butyl] -4-oxo-1-azetidinone
Stage A: [S-(R*S*)]-2-[4-[[4-benzyloxycarbonyl)piperazine-1-yl]carbonyl] phenoxy]-((3,3-diethyl-N-[1-(3,4-methylenedioxyphenyl)butyl]-4-oxo-1-azetidinone
During the reaction of [S-(R*S*)]-4-(((3,3-Diethyl-1-((3,4-methylenedioxyphenyl)butylamino)carbonyl)-4-oxo-2-azetidine)oxy)benzoyl chloride (0.41 mmol) obtained by the method of example 11 from N-(benzyloxycarbonyl)piperazine (0.77 mmol) and diisopropylethylamine (1.6 mmol) as described in example 23, to obtain 290 mg of the target compound.Stage B: [S-(R*S*)]-2-[4-(piperazine-1-yl]carbonyl]-phenoxy]-((3,3-diethyl-N-[1-(3,4-methylenedioxyphenyl)butyl]-4-oxo-1-azetidinone
A solution of 250 mg of the material obtained in stage a of example 26, hydrogenizing under pressure of 40 pounds/inch2in the presence of 50 mg of 10% Pd/C for 16 hours the Reaction mixture% TFU/10% methanol/88% ethyl acetate and up to 150 mg of the target product.Analytical data for C30H38N4O63H2O
Calculation (in %): C - 59,59, H - 7,33, N - 9,29.Found: C - 59,66, H - 7,65, N Being 9.61. 1. Substituted azetidinone General formula (I)
< / BR>or their pharmaceutically acceptable salt,
where R is C1-6alkyl;
R1- C1-6alkyl;
M - C1-6alkyl;
Raand Rbeach is hydrogen;
R2and R3each independently from each other hydrogen, C1-6alkyl, or R2and R3can be combined with each other to form methylenedioxy;
R4represents: (a) group
< / BR>or b) group
< / BR>where Rx- carboxy C1-6alkyl, benzyloxycarbonyl-C1-3alkyl or tert-butoxycarbonyl1-3alkyl, where Q represents a covalent bond or a group
< / BR>thus R5and R6each is hydrogen;
Y represents a
< / BR>R12is hydrogen or C1-3alkyl;
R7and R8each independently from each other: (a) hydrogen; (b) C1-6alkyl; (C) C1-6alkoxyl2-3alkyl; (g) hydraxis2-6alkyl; (e) polyhedrosis2-6alkyl; (e) carboxamido1-6alkyl; (W) C1-6alkanoyl; (C) substituted phenyl or panels1-6cycloalkenyl; (l) heteroaryl1-6alkyl, with heteroaryl includes pyridinyl and imidazolyl; (m) carboxin1-6alkyl; (n) carbos1-6alkoxy, C1-3alkyl; (o) phenylsulfonyl; (p) C1-6alkylsulfonyl; (p) benzyloxy; (C) morpholinyl1-3alkylsulfonyl; (t) tetrahydropyranyl; (u) aminos1-3alkylsulfonyl, where the amino group may be mono - or tizamidine C1-6by alkyl; (f) aminocarbonyl, where the amino group may be mono - or tizamidine C1-6by alkyl; (x) aminocarboxylate2-6alkyl, where the amino group may be mono - or tizamidine C1-6by alkyl; (C) azabicyclo containing 7 to 12 atoms; (h) dis1-3alkylamino2-6alkyl, where the amino group may be mono - or tizamidine C1-6by alkyl; (W) bicycloalkyl containing 7 to 12 atoms; (y) C3-10cycloalkyl, substituted C1-6by alkyl; (b) pyrazolidine; (AA) substituted or unsubstituted, piperidinyl, in which the Deputy may be C1-3alkyl, hydroxys1-3alkylbenzene, carboxamido - or amino group, the amino group may be mono - or tizamidine C1-6by alkyl; (BB) substituted pyrrolidinyl, in which the Deputy is carboxamido - or amino group, the amino group may butylbenzyl, and mono - or disubstituted by benzyl, mono - or disubstituted pyridylmethyl, in which the substituents are X1or X2while X1represents: (1) hydrogen; (2) holograph; (3) C1-6alkyl; (4) Gialos1-6alkyl; (5) C2-6alkenyl; (6) hydraxis1-6alkyl; (7) C1-6alkylsulphonyl; (8) C1-6alkylcarboxylic; (9) CN; (10) CF3; (11) CH3O; (12) an amino group, this amino group may be mono - or tizamidine C1-6by alkyl; (13) carboxypropyl or (14) vinylsulfonylacetamido;
X2- hydrogen, holograph or C1-6alkyl;
n = 1, 2, 3, 4 or 5;
R9is selected from the group including hydrogen, C1-4alkyl and C1-3alkoxyl2-3alkyl; or phenyl, panels1-3alkyl, pyridyl and pyridyl-C1-3alkyl;
R10and R11each chosen independently from one another from the group comprising hydrogen, C1-6alkyl and C1-3alkoxyl1-3alkyl or represent both together O=; or
R7and R8together with the nitrogen to which they are attached, form a mono - or disubstituted ring selected from the group consisting of (1) piperidinyl or homopiperazine; (2) piperazinil; (3) morpholinyl, thiomorpholine or 1,1-dioxo-4-Timor the atoms; (9) Azospirillum; (10) tetrazolyl; (11) pyrazolidine; (12) azetidine or (13) diazabicyclo containing 7 to 12 atoms, where each of the substituents is selected from the group consisting of hydrogen and C1-3of alkyl, benzyloxycarbonyl, panels1-3alkylaminocarbonyl, hydroxys1-3of alkyl, C1-6alkoxy, C1-4allyloxycarbonyl, aminocarbonyl where the above-mentioned amino group may be mono - or tizamidine C1-6the alkyl, and carbonyl group; or
R8and R9together form a mono - or disubstituted monocyclic ring containing 6 to 7 atoms comprising 2 nitrogen atom; or
R9and R12together form a mono - or disubstituted saturated monocyclic ring containing 5, 6 or 7 atoms and containing one nitrogen atom; or
R10and R12together with the carbon atoms to which they are attached, form a mono - or disubstituted monocyclic ring containing 5, 6 or 7 carbon atoms.2. Substituted azetidinone General formula (I)
< / BR>or their pharmaceutically acceptable salt,
where R is C1-6alkyl;
R1- C1-6alkyl;
M - ethyl, propyl, butyl, pentyl or hexyl;
Raand Rbeach independently from each other: 1-6alkoxy; (5) amino2-3allyloxycarbonyl, where the amino group may be mono - or tizamidine C1-6-alkyl; (6) amino2-3alkylaminocarbonyl, where the amino group may be mono - or tizamidine C1-6by alkyl; (7) a hydroxy-group; (8) aminocarbonyl, where the amino group may be mono - or tizamidine C1-6-alkyl; (9) hydroxymethyl; (10) aminocarboxylate1-3alkyl, where the amino group may be mono - or tizamidine C1-6-alkyl; (11) cyano; (12) morpholinosydnonimine; or (13) morpholinoethyl;
R3- (1) C1-6alkyl; (2) holograph; (3) C1-6alkoxy; (4) amino2-3allyloxycarbonyl, where the amino group may be mono - or tizamidine C1-6-alkyl; (5) amino2-3alkylaminocarbonyl, where the amino group may be mono - or tizamidine C1-6by alkyl; (6) a hydroxy-group; (7) aminocarbonyl, where the amino group may be mono - or tizamidine C1-6by alkyl; (8) hydroxymethyl; (9) aminocarboxylate1-3alkyl, where the amino group may be mono - or tizamidine C1-6-alkyl; (10) cyano; (11) morpholinosydnonimine or (12) morpholinoethyl, provided that R2and R3can be combined with each other to form methylenedioxy;
R4alkyl or tert-butoxycarbonyl1-3alkyl,
where Q is a covalent bond or a group
< / BR>where R5and R6each is hydrogen;
Y represents a
< / BR>or a covalent bond;
R12is hydrogen or C1-3alkyl;
R7(a) - ethyl, propyl, butyl, pentyl or hexyl; (b) C1-6alkalosis2-3alkyl; (C) hydraxis2-6alkyl; (g) polyhydroxy2-6alkyl; (d) carboxamido1-6alkyl; (e) C1-6alkanoyl; (g) substituted phenyl or panels1-6alkyl, and the substituents represented by X1and X2as defined below; (C) C2-6alkenyl; (and) C6-10cycloalkenyl; (K) heteroaryl1-6alkyl, these heteroaryl includes pyridinyl and imidazolyl; (l) carboxin1-6alkyl; (m) carbos1-6alkoxyl1-3alkyl; (n) phenylsulfonyl; (o) C1-6alkylsulfonyl; (p) benzyloxy; (p) morpholinyl1-3alkylsulfonyl; (C) tetrahydropyranyl; (t) aminos1-3alkylsulfonyl, amino group may be mono - or tizamidine C1-6by alkyl; (u) aminocarbonyl, and the amino group may be mono - or tizamidine C1-6by alkyl; (f) aminocarboxylate2-6alkyl, amino group may be mono - or tizamidine C1-61-6by alkyl; (h) bicycloalkyl containing 7 to 12 atoms; (W) C3-10cycloalkyl, possibly substituted C1-6by alkyl; (y) pyrazolidine; (b) a substituted or an unsubstituted piperidinyl or pyrrolidinyl, where the substituents may be C1-3alkyl, hydroxys1-3alkylbenzene, carboxamido - or amino group, the amino group may be mono - or tizamidine C1-6by alkyl; (AA) substituted pyrrolidinyl, in which the Deputy is carboxamido - or amino group, the amino group may be substituted C1-6by alkyl; (BB) pyrimidinyl; (IV) phosphono1-6alkyl or (gg) alpha-C1-3alkylbenzene, and mono - or disubstituted by benzyl or mono - or disubstituted pyridylmethyl, while the substituents are X1or X2;
R8(a) hydrogen or C1-6alkyl; (b) C1-6alkalosis2-3alkyl; (C) hydraxis2-6alkyl; (g) polyhydroxy2-6alkyl; (d) carboxamido1-6alkyl; (e) C1-6alkanoyl; (g) substituted phenyl or panels1-6alkyl, and the substituents represented by X1and X2as defined below; (C) C2-6alkenyl; (and) C6-10cycloalkenyl; (K) heteroaryl1-6alkyl, these heteroaryl selected from the group on sulfonyl; (o) C1-6alkylsulfonyl; (p) benzyloxy; (p) morpholinyl1-3alkylsulfonyl; (C) tetrahydropyranyl; (t) aminos1-3alkylsulfonyl, amino group may be mono - or tizamidine C1-6by alkyl; (u) aminocarbonyl, and the amino group may be mono - or tizamidine C1-6by alkyl; (f) aminocarboxylate2-6alkyl, amino group may be mono - or tizamidine C1-6by alkyl; (x) azabicyclo containing 7 to 12 atoms; (C) dis1-3alkylamino2-6alkyl, amino group may be substituted C1-6by alkyl; (h) bicycloalkyl containing 7 to 12 atoms; (W) C3-10cycloalkyl, possibly substituted C1-6by alkyl; (y) pyrazolidine; (b) a substituted or an unsubstituted piperidinyl, in which the Deputy may be C1-3alkyl, hydroxys1-3alkylbenzene, carboxamido - or amino group, the amino group may be substituted C1-6by alkyl; (AA) substituted pyrrolidinyl, in which the Deputy is carboxamido - or amino group, the amino group may be substituted C1-6by alkyl; (BB) pyrimidinyl; (IV) phosphono1-6alkyl or (gg) alpha-C1-3alkylbenzene, and mono - or disubstituted by benzyl or mono - or disubstituted pyridylmethyl, the 1-6alkyl; (4) Gialos1-6alkyl; (5) C2-6alkenyl; (6) hydraxis1-6alkyl; (7) C1-6alkylsulphonyl; (8) C1-6alkylcarboxylic; (9) CN group; (10) CF3; (11) CH3O; (12) amino group, this amino group may be mono - or tizamidine C1-6by alkyl; (13) carboxypropyl or (14) vinylsulfonylacetamido;
X2- hydrogen, holograph or C1-6alkyl;
n = 1, 2, 3, 4 or 5;
R9selected from the group including hydrogen, C1-4alkyl and C1-3alkoxyl2-3alkyl; or phenyl, panels1-3alkyl, pyridyl and pyridyl1-3alkyl;
R10and R11each chosen independently from one another from the group comprising hydrogen, C1-4alkyl and C1-3alkoxyl1-3alkyl, or represent both together O=; or
R7and R8together with the nitrogen atom to which they are attached, form a mono - or disubstituted ring selected from the group consisting of (1) piperidinyl or homopiperazine; (2) piperazinil; (3) morpholinyl, thiomorpholine or 1,1-dioxo-4-thiomorpholine; (4) pyrrolidinyl; (5) peril; (6) imidazolyl; (7) triazolyl; (8) rich azabicyclo containing 7 to 12 atoms; (9) Azospirillum; (10) tetrazolyl; (11) pyrazolidine; (12) azetidinol or (13) Diaz is Yes and C1-3of alkyl, benzyloxycarbonyl, panels1-3alkylaminocarbonyl, pyrrolidinyl, hydroxys1-3of alkyl, C1-6alkoxy, C1-4allyloxycarbonyl, aminocarbonyl where the above-mentioned amino group may be mono - or tizamidine C1-6the alkyl, and carbonyl group; or
R8and R9together form a mono - or disubstituted saturated monocyclic ring containing 6 to 7 atoms comprising 2 nitrogen atom; or
R9and R12together form a mono - or disubstituted saturated monocyclic ring containing 5, 6 or 7 atoms and one nitrogen atom; or
R10and R12together with the carbon atoms to which they are attached, form a mono - or disubstituted monocyclic ring containing 5, 6 or 7 carbon atoms.3. The compound of formula I under item 1, where Q is a covalent bond; Y is a
< / BR>R4represents a
< / BR>4. Connection on p. 3, where R is a C1-6alkyl; R1- C1-6alkyl; M - C1-6alkyl; Raand Rbeach hydrogen; R2and R3each represents independently from each other: (1) hydrogen; (2) C1-6alkyl; or R2and R3can be combined with each other with the formation of met>BR>R12is hydrogen or C1-3alkyl; R7and R8each independently from each other - (a) hydrogen; (b) C1-6alkyl; (C) C1-6alkoxyl2-3alkyl; (g) hydraxis2-6alkyl; (d) carboxamido1-6alkyl; (e) C1-6alkanoyl; (f) phenyl or panels1-6alkyl; (C) C2-6alkenyl; (and) C6-10cycloalkenyl; (K) heteroaryl1-6alkyl, these heteroaryl includes pyridinyl imidazolyl; (l) carboxin1-6alkyl; (m) C1-6alkylsulfonyl; (h) benzyloxy; (o) morpholinyl1-3alkylsulfonyl; (p) aminos1-3alkylsulfonyl, amino group may be mono - or tizamidine C1-6by alkyl; (p) aminocarbonyl, and the amino group may be mono - or tizamidine C1-6by alkyl; (C) aminocarboxylate2-6alkyl, amino group may be substituted C1-6by alkyl; (t) pyrazolidine; (u) piperidinyl; (f) pyrimidinyl; (x) alpha-C1-3alkylbenzene, and mono - or disubstituted by benzyl or mono - or disubstituted pyridylmethyl, while the substituents are X1or X2; where X1- (1) hydrogen; (2) holograph; (3) C1-6alkyl; (4) Gialos1-6alkyl; (5) C2-6alkenyl; (6) hydraxis1-6alkyl; (7) C1-6alkylsulphonyl; (8) C1-6Alki is hydrogen, holograph or C1-6alkyl; n = 1, 2, 3, 4, or 5; each of R10and R11chosen independently of one another from the group consisting of hydrogen, C1-4the alkyl and C1-3alkoxy-C1-3of alkyl; or R7and R8together with the nitrogen to which they are attached, form a mono - or disubstituted ring selected from the group including: (1) piperidinyl; (2) piperazinil; (3) morpholinyl; (4) pyrrolidinyl; (5) peril; (6) imidazolyl; (7) triazolyl; (8) tetrazolyl; (9) pyrazolidine or (10) azetidinol, each of the substituents is selected from the group consisting of hydrogen and C1-3alkyl, benzyloxycarbonyl, panels1-3alkylaminocarbonyl, hydroxys1-3alkyl, C1-6alkoxy, C1-4allyloxycarbonyl and oxoprop; or R10and R12together with the carbon atoms to which they are attached, form a monocyclic mono - or disubstituted ring containing 5, 6 or 7 carbon atoms.5. Connection on p. 4, where R is a C1-3alkyl; R1- C1-3alkyl; M - C1-6alkyl; R2(a) hydrogen; (b) C1-6alkyl; R3is hydrogen or R2and R3together with the formation of methylenedioxy; R7and R8independently from each other chosen from the group consisting of: the mi are the X1and X2while X1is hydrogen, and X2(a) hydrogen; (b) galegroup or (b) C1-3alkyl; n = 1, 2, or 3, and R10and R11chosen independently of one another from the group comprising hydrogen, C1-4alkyl and C1-3alkoxyl1-3alkyl; or R7and R8form together a substituted ring selected from the group consisting of (a) piperidinyl; (b) piperazinil and (C) morpholinyl; or R10and R12together with the carbon atoms to which they are attached, form a mono - or disubstituted monocyclic ring containing 5, 6 or 7 carbon atoms.6. Connection on p. 5, where R is methyl or ethyl; R1is methyl or ethyl; M is - C1-4alkyl; R2(a) hydrogen; (b) C1-3alkyl, and R3is hydrogen or R2and R3together with the formation of methylenedioxy; n = 1 or 2; R10choose from the group consisting of: (a) C1-3alkyl; (b) C1-3alkoxyl2-3alkyl; (C) hydrogen; R7and R8independently from each other chosen from the group consisting of: (a) hydrogen; (b) C1-3alkyl; (C) C1-3alkoxy-C2-3alkyl; or R7and R8together with the nitrogen atom to which they are attached, form a substituted ring selected from the group consisting of: (a) piperidyl mono - or disubstituted monocyclic ring, containing 5, 6 or 7 carbon atoms.7. Connection on p. 1, where Q is a covalent bond; R4represents a
< / BR>Y represents a
< / BR>8. Connection on p. 7, where R is a C1-6alkyl; R1- C1-6alkyl; M - C1-6alkyl; Raand Rbeach hydrogen; R2and R3each independently of one another is (1) hydrogen; (2) C1-6alkyl, or R2and R3can be combined together to form methylenedioxy; R4represents a
< / BR>where Q is a covalent bond; or Y is a
< / BR>R12is hydrogen or C1-3alkyl; R7and R8each independently from each other: (a) hydrogen; (b) C1-6alkyl; (C) C1-6alkoxyl2-3alkyl; (g) hydraxis2-6alkyl; (d) carboxamido1-6alkyl; (e) C1-6alkanoyl; (f) phenyl or panels1-6alkyl; (C) C2-6alkenyl; (and) C6-10cycloalkenyl; (K) heteroaryl1-6alkyl, these heteroaryl includes pyridinyl, imidazolyl; (l) carboxin1-6alkyl or Carbo1-6alkoxyl1-3alkyl; (m) C1-6alkylsulfonyl; (h) benzyloxy; (o) morpholinyl1-3alkylsulfonyl; (p) aminos1-3alkylsulfonyl, amino group may be mono - or disame is m; (C) aminocarboxylate2-6alkyl, amino group may be substituted C1-6by alkyl; (t) pyrazolidine; (u) piperidinyl; (f) pyrimidinyl; (x) C3-7cycloalkyl; (C) alpha-C1-3alkylbenzene, or mono - or disubstituted by benzyl or mono - or disubstituted pyridylmethyl, while the substituents are X1or X2; where X1- (1) hydrogen; (2) holograph; (3) C1-6alkyl; (4) Gialos1-6alkyl; (5) C2-6alkenyl; (6) hydraxis1-6alkyl; (7) C1-6alkylsulphonyl; (8) C1-6alkylcarboxylic; (9) dis1-3alkylamino or (10) carboxypropyl; X2- hydrogen, holograph or C1-6alkyl; n = 1, 2, 3 or 4; R9selected from hydrogen, C1-4the alkyl and C1-3alkoxy-C2-3of alkyl; each of R10and R11chosen independently of one another from the group consisting of hydrogen, C1-4the alkyl and C1-3alkoxy-C1-3of alkyl; or R7and R8together with the nitrogen to which they are attached, form a mono - or disubstituted ring selected from the group including: (1) piperidinyl; (2) piperazinil; (3) morpholinyl; (4) pyrrolidinyl; (5) peril; (6) imidazolyl; (7) triazolyl; (8) tetrazolyl; (9) pyrazolidine or (10) azetidinol, each of the substituents is selected from group-3alkyl, C1-6alkoxy, C1-4allyloxycarbonyl and oxoprop; or R8and R9together form a saturated mono - or disubstituted monocyclic ring containing 6 or 7 carbon atoms and containing 2 nitrogen atom; such ring selected from piperazinil and homopiperazine; or R9and R12together form a mono - or disubstituted saturated monocyclic ring containing 5, 6 or 7 atoms, the said ring consists of one nitrogen atom; or R10and R12together with the carbon atoms to which they are attached, form a mono - or disubstituted monocyclic ring containing 5, 6 or 7 carbon atoms.9. Connection on p. 8, where R is a C1-3alkyl; R1- C1-3alkyl; M - C1-6alkyl; R2(a) hydrogen; (b) C1-6alkyl, and R3is hydrogen or R2and R3together with the formation of methylenedioxy; R7and R8independently from each other chosen from the group consisting of: (a) hydrogen; (b) C1-3alkyl; (C) C1-3alkoxyl2-3alkyl; (g) hydraxis2-3alkyl; (e) carbos1-4alkoxymethyl; (e) substituted benzyl in which the substituents are X1and X2while X1is hydrogen, and X2- (mo apart from the group, including hydrogen, C1-4alkyl and C1-3alkoxyl2-3alkyl; or R7and R8together with the nitrogen atom to which they are attached, form a substituted ring selected from the group consisting of: (a) piperidinyl; (b) piperazinil and (C) morpholinyl; or R8and R9together form a mono - or disubstituted saturated monocyclic ring containing 5, 6 and 7 carbon atoms and containing two atoms of nitrogen.10. Connection on p. 9, where R is methyl or ethyl; R1is methyl or ethyl; M is - (a) C1-4alkyl; R2(a) hydrogen; (b) C1-3alkyl; R3is hydrogen or R2and R3together form methylenedioxy; n = 1 or 2; R9and R10choose from the group consisting of: (a) hydrogen, (b) C1-3alkyl; (C) C1-3alkoxyl1-3alkyl; R7and R8independently from each other chosen from the group consisting of: (a) hydrogen; (b) C1-3alkyl; (C) C1-3alkoxyl2-3alkyl; (g) hydroxyethyl; (e) carboethoxy, or R7and R8together with the nitrogen to which they are attached, form a mono - or disubstituted monocyclic ring, which is piperidinyl or morpholinyl, with the said ring may be substituted by hydrogen or stands; or R8and R
< / BR>and R7- (b) the ethyl, propyl, butyl, pentyl and hexyl; (C) cyclopropyl; (g) C1-3alkoxyl2-3alkyl; (d) hydroxyethyl; (e) carbetimer; R8(a) - (C1-3alkyl; (b) cyclopropyl; (C) C1-3alkoxyl1-3alkyl; (g) hydroxyethyl; (e) carbetimer; or R7and R8together with the nitrogen atom to which they are attached, form a mono - or disubstituted monocyclic ring, which is piperidinyl or morpholinyl, with the said ring may be substituted by hydrogen or stands.12. Connection on p. I of the formula
< / BR>in which A represents (1) -CH2CH2N(CH3)2; (2) -CH2CO2H; (3) -CH2-C(O)N(CH2CH2OH)2; (4) -CH2-C(O)N(CH3)CH2C(O)NH2; (5) -CH2C(O)NH-C(CH2OH)3; (6) -CH2C(O)N(CH3)2; (7) -CH2CH2N(CH3)Ac; (8) -CH(CH32; (12) -CH2CH2CH2N(CH3)2; (13) -CH2CH2N(Et)2; (14) -CH2CH2(4-morpholinyl);
(15) -CH2CH2CH2CH2N(CH3)2; (16) -CH2C(O)-PrO-NHCH2Ph; (17) -CH2C(CH3)2N(CH3)2; (18) -CH2CH2N(i-Pr)2; (19) -CH2CH2N(n-Bu)2; (20) -CH2CH2CH2CH2CH2CH2N(CH3)2; (21) -CH2CH2(1-piperazinil); (22) -CH2CH2(4-methyl-1-piperazinil); (23) -CH2CH2N(Ph)2; (24) -CH2CH2N(CH2CH= CH2)2; (25) -CH2CH(Ph)N(CH3)2or (26) -CH2CH2N(CH3)CH2Ph.13. Connection on p. 1 formula
< / BR>in which A represents (1) -CH2CH2N(CH3)2; (2) -CH2CH2CH2N(CH3)2; (3) -CH2CH2N(Et)2; (4) -CH2CH2-(4-morpholinyl);
(5) -CH(CH3)CH2N(CH3)2; (6) -CH2C(CH3)2N(CH3)2or (7) -CH2CH2N(CH3)CH2Ph. 14. Connection on p. 2 of the formula:
< / BR>in which A represents (1) -N(CH2CH2OH)2; (2) 4-methyl-1-piperazinil; (3) 4-morpholinyl; (4) -NHCH2CH2N(CH3)2; (5) CH2(-4-pyridyl); (8) -NHCH2CO2H; (9) -NHCH(CH3)CO2H; (10) -NHCH2C(O)N(CH2CH2OH)2; (11) -N(CH3)CH2CO2H; (12) -NHCH(CH3)C(O)N(CH2CH2OH)2; (13) -N(CH3)CH2C(O)N(CH2CH2OH)2; (14) -N(CH3)CH2CH2-(4-morpholinyl); (15) -N(CH3)CH2CH2N(CH2CH2OCH3)2;
(16) -N(CH3)CH2CH2N(Et)2; (17) -N(CH3)CH2CH2CH2N(CH3)2; (18) -NHCH2CH(CH3)N(CH3)2; (19) -N(CH3)CH2CH2N(i-Pr)2; (20) -N(n-Pr)2; (21) -N(Et)2; (22) 3 chloraniline-; (23) 3-methoxyaniline-; (24) 4-foronline-; (25) -N(CH3)CH2CH2CH2CO2H; (26) -N(CH3)CH2CH2CH2C(O)NHSO2Ph; (27) -N(CH3)CH2CH2CH2N(CH3)CH2Ph; (28) -N(CH3)2; (29) -N(CH3)CH2Ph; (30) -N(CH3)CH2CH2N(CH3)CH2Ph; (31) -NH-O-CH2Ph; (32) -N(CH3)(4-carboxyphenyl) or (33) -N(CH3)(4-benzensulfonamidelor).15. Connection on p. 2
< / BR>in which A represents (1) -NHCH2CH2N(CH3)2; (2) -NH-CH2CO2H; (3) -N(CH3)CH2CH2N(CH3)2; (4) -N(Et)CH3)CH2CH2-(4-morpholinyl); (8) -N(CH3)CH2CH2N(CH2CH2OCH2)2; (9) -N(CH3)CH2CH2N(Et)2; (10) -N(Ph)CH2CH2N(CH3)2; (11) -N(CH3)CH2CH2CH2N(CH3)2; (12) -NHCH2CH2N(i-Pr)2; (13) -N(CH3)CH2CH2N(iPr)2; (14) -NHCH2CH2-(1-piperidinyl); (15) -N(CH3)CH2CH2-(1-piperidinyl); (16) -N(CH3)CH2CH2NHCH3; (17) -N(CH3)CH2CH2N(CH3)Ac; (18) -NHCH2CH2-(1-pyrrolidinyl); (19) -N(CH3)CH2CH2-(1-pyrrolidinyl); (20) -NHCH2CH2-(1H-1,2,4-triazole-4-yl); (21) -NH-CH2CH2-(1-imidazolyl); (22) -NH-CH2CH2-(2H-tetrazol-2-yl); (23) -NH-CH2CH2-(1H-tetrazol-1-yl); (24) -N(CH3)CH2CH2N(CH3)Ac; (25) -N(CH3)CH2CH2N(CH3)C(O)NHCH3; (26) -N(CH3)CH2CH2N(CH3)SO2CH3; (27) -NHCH2CH2-(1,1-dioxo-4-thiomorpholine); (28) -4-dimethylaminobenzylidene; (29) 3-dimethylaminopyridine; (30) -N(CH3)CH2CH2-(1,1-dioxo-4-thiomorpholine); (31) 4-dimethylaminopyridine; (32) -NHCH2CH2-(1-benzyl-1H-imidazol-2-yl); (33) -N(CH3)CH2CH2-(2-pyridyl); (34) -NHCH2CH2-(4-benzopyranyl); (37) -N(CH3)CH2CH2N(CH3)CH2Ph; (38) -N(n-Pr)2; (39) -N(Et)2; (40) -N(CH3)CH2CH2-(4-oxo-1-piperidinyl); (41) -N(Et)CH2CH2-(1-piperidinyl); (42) -N(CH2Ph)CH2CH2-(1-piperidinyl); (43) 4 foronline; (44) 3-chloraniline; (45) 3-methoxyaniline; (46) -N(CH2Ph)CH2CH2N(CH3)2; (47) -N(3-picolyl)-CH2CH2-(1-piperidinyl); (48) -NHCH(CH3)CH2CH2CH2N(Et)2; (49) -NHCH2CH2-(2-S-hydroxymethyl-1-pyrrolidinyl); (50) -N(CH3)CH2CH2-(4-tertbutoxycarbonyl-1-piperazinil); (51) -N[CH2CH2N(CH3)2]2; (52) -N[CH2CH2N(Et)2]2; (53) -N(CH3)CH2CH2N(CH3)-(3-picolyl); (54) -3,5-dimethyl-1-piperazine; (55) -N(CH3)CH2CH2N(CH3)-(4-picolyl); (56) -N(CH3)CH2CH2N(CH3)-(2-picolyl); (57) -N(CH3)CH2CH2-(1-piperazinil); (58) 1-homopiperazine; (59) -N(CH3)CH2CH2N(CH3)CH2CH2Ph; (60) -N(CH3)CH2-[CH(OH)]4CH2OH; (61) -N(CH3)CH2CH2N(CH3)CH(CH3)Ph; (62) -N(CH3)CH2CH2N(CH2Ph)2; (63) 1-ethyl-3-piperidylamine; (64) -N(CH3)CH2CH2CH2C(O)NHSO3Ph; (65) -N(CH/SUB>Ph; (67) -N(CH3)-(CH2)6-N(CH3)CH2Ph; (68) -N(CH3)CH2CH2OH; (69) -N(CH3)CH2CH2OC(O)N(CH3)2; (70) -N(CH3)CH2CH2N(CH3)CH2CO2-t-Bu; (71) -N(CH3)-(1-ethyl-3-piperidinyl); (72) -N(CH3)CH2CH2N(CH3)-(tetrahydro-2H-Piran-2-ylmethyl); (73) -2,2,6,6-tetramethylpiperidine-4-ylamine; (74) -N(CH3)-(4-carboxyphenyl); (75) -N(CH3)CH2CH2N(CH3)-(4-cyanobenzyl); (76) -N(CH3)CH2CH2N(CH3)-(4-methylbenzyl); (77) -N(CH3)CH2CH2N(CH3)-(3-cyanobenzyl); (78) -N(CH3)CH2CH2N(CH3)-(4-trifloromethyl); (79) -N(CH3)CH2CH2N(CH3)-(3-trifloromethyl); (80) -N(CH3)CH2CH2N(CH3)-(cyclopropylmethyl); (81) -N(CH3)CH2CH(Ph)N(CH3)2; (82) -N(CH3)CH2Ph; (83) -N(CH3)-(1-benzyl-3-piperidinyl); (84) -N(3-picolyl)CH2CH2N(CH3)CH2Ph; (85) -N(CH3)CH2CH2N(CH3)-(4-methoxybenzyl); (86) -N(4-picolyl)CH2CH2N(CH3)CH2Ph; (87) -N(2-picolyl)CH2CH2N(CH3)CH2Ph; (88) -N(CH3)CH2CH2N(CH3)-(2,4-dimethylbenzyl); (89) -N(CH3)CH2CH2-(2,6-dimethyl-4-morpholinyl); (90) 4 morpholine is 3)-(3-terbisil); (94) -N(CH3)CH2CH2N(CH3)-(2-Chlorobenzyl); (95) -N(CH3)CH2CH2N(CH3)-(3-methoxybenzyl); (96) -N(CH3)-(1-benzyl-4-piperidinyl); (97) -N(CH3)CH2CH2N(CH3)-(2-substituted); (98) -N(CH3)-(4-piperidinyl); (99) 5-methyl-2,5-diazabicyclo[2,2,1]hept-2-yl; (100) -N(CH3)CH2CO2H; (101) -N(CH3)CH2CH2CH2N(CH3)CH2CH3; (102) -N(CH3)-(1-methyl-4-piperidinyl); (103) -N(CH3)-(1-propyl-4-piperidinyl); (104) -N(CH3)-(1-ethyl-4-piperidinyl); (105) -N(CH3)CH2CH(CH3)N(CH3)CH2Ph; (106) -N(CH3)CH2CH(CH3)N(CH3)2; (107) -N(CH3)CH2CH2NH-(2-substituted); (108) -N(CH3)CH2CH2N(CH3)-(6,6-dimethylbicyclo-[3,1,1] -hept-2-yl; (109) -N(CH3)CH2CH2N(CH3)-(1-cyclohexen-1-yl); (110) -N(CH3)CH2CH2NHC(CH3)2CH=CH2; (111) 2-S-carboxamido-1-pyrrolidinyl; (112) 2-hydroxymethyl-1-piperidinyl; (113) 3-dimethylamino-1-pyrrolidinyl; (114) -N(CH3)CH2CH2N(CH3)(cyclohexylmethyl); (115) -N(CH3)CH2CH2N(CH2CH= CH2)C(CH3)2CH= CH2; (116) -N(CH3)CH2CH2N(CH3)(4-ethylcyclohexyl); (117) -N(CH3)CH2CH2N(CH<CH2N(CH3)(cyclohexyl); (120) -N(CH3)CH2CH2N(CH3)CH2C(O)N(CH3)2;
(121) -N(CH3)CH2CH2N(CH3)(cyclohexylmethyl) or (122) -NHCH2CH2N(Et)CH2CH2OCH3.16. Connection on p. 1 formula
< / BR>in which R represents (1) -CH3; (2) 4-forfinal; (3) 3-chlorophenyl; (4) phenyl; (5) benzyl; (6) hydrogen; (7) i-Pr; (8) i-Bu; (9) -CH2CO2Et; (10) -CH2CO2H; (11)Et; (12) Pr; (13) 2-pyrimidinyl; (14) -CH2CH2OC(O)NHCH3; (15) cyclopropyl or (16) -CH2CH2OH.17. Connection on p. 2 of the formula
< / BR>in which values of n and A are given in table. A.18. Connection on p. 2 of the formula
< / BR>in which n, R2and A are given in table. B.19. Connection on p. 2 of the formula
< / BR>in which n, R3and A are given in table. IN
20. Connection on p. 2 of the formula
< / BR>in which n, R2, R3and A are given in table. ,21. Connection on p. 1 formula
< / BR>in which R2, R6and A are given in table. D.22. Connection on p. 1, selected from the group including:
(a) tert-butoxycarbonylmethyl[S-(R*, S*)] 4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-aseigo)carbonyl)-4-oxo-2-azetidine)oxy)benzoate;
(C) 1-methyl-2-oxo-2-(phenylmethoxy)ethyl(2S-(1(S*), 2R*, R)))4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoate;
(g) 1-carboxyethyl[S-(R*,S*)]4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoate;
(d) 2-(diethylamino)-1-methyl-2-oxoethyl[S-(R*, S*)] -4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoate;
(e) [S-(R*,S*)]-1-(((4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoyl)oxy)acetyl)-L-Proline;
(W) [S-(R*,S*)]-1-(((4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoyl)oxy)acetyl-N-benzyl-L-prolinamide;
(C) 2-(dimethylamino)ethyl[S-(R*, S*)] -4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoate;
(and) 1-dimethylamino-2-propyl[S-(R*, S*)]-4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoate;
(K) 3-dimethylamino-1-propyl[S-(R*, S*)]-4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoate;
(l) 2-diethylaminoethyl[S-(R*, S*)] -4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoate;
(m) 2-(1-(4-morpholino)ethyl) - [S-(R*, S*)]-4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-l)-4-oxo-2-azetidine)oxy)benzoate;
(o) 2-dimethylamino-2-methyl-1-propyl[S-(R*, S*)]-4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoate;
(p) 2-(diisopropylamino)ethyl[S-(R*, S*)] -4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoate;
(b) benzyl[S-(R*,S*)]-4-(2-((4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoyl)oxyethyl)-1-piperazine-carboxylate;
(C) 2-(dibutylamino)ethyl[S-(R*, S*)] -4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoate;
(t) [S-(R*, S*)]-6-(dimethylamino)hexyl-4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoate;
(u) 2-(4-methyl-1-piperazinil)ethyl[S-(R*,S*)]-4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoate;
(f) 2-(diphenylamino)ethyl[S-(R*, S*)] -4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoate;
(x) 2-(di-2-propylamino)ethyl[S-(R*, S*)]-4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoate;
(C) 2-(dimethylamino)-2-phenylethyl[S-(R*, S*)]-4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)benzoate;
(h) 2-(methyl(phenylmethyl)amino)ethyl[S-(R*, S*)] -4-((3,3-diethyl-1-(((1-(4-were)butyl) who yl)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)-2,6-dimethyl-benzoate;
(y) 2-(diethylamino)ethyl[S-(R*, S*)] -4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)-2,6-dimethyl-benzoate;
(b) 2-(bis-(1-methylethyl)amino)ethyl[S-(R*, S*)] -4-((3,3-diethyl-1-(((1-(4-were)butyl)amino)carbonyl)-4-oxo-2-azetidine)oxy)-2,6-dimethyl-benzoate;
23. Connection on p. 1, selected from the group including:
(a) [S-(R*,S*)]-2-(4-(((2-dimethylamino)ethyl)methylamino)carbonyl)phenoxy)-3,3-diethyl-N-(1-(4-were)butyl)-4-oxo-1-azetidinone;
(b) [S-(R*,S*)]-2-(4-(((2-dimethylamino)ethyl)methylamino)carbonyl)phenoxy)-3,3-diethyl-N-(1-(3,4-methylenedioxyphenyl)butyl)-4-oxo-1-azetidinone;
(C) [S-(R*, S*)]-2-(4-((4-methylpiperazin-1-yl)carbonyl)phenoxy)-3,3-diethyl-N-(1-(4-were)butyl)-4-oxo-1-azetidinone;
(g) [S-(R*, S*)]-2-(4-((4-methylpiperazin-1-yl)carbonyl)phenoxy)-3,3-diethyl-N-(1-(3,4-methylenedioxyphenyl)butyl)-4-oxo-1-azetidinone;
(d) [S-(R*, S*)]-2-(4-((4-cyclopropylmethyl-1-yl)carbonyl)phenoxy)-3,3-diethyl-N-(1-(4-were)butyl)-4-oxo-1-azetidinone;
(e) [S-(R*, S*)]-2-(4-((4-cyclopropylmethyl-1-yl)carbonyl)phenoxy)-3,3-diethyl-N-(1-(3,4-methylenedioxyphenyl)butyl)-4-oxo-1-azetidinone;
(W)[S-(R*, S*)] -2-(4-((piperazine-1-yl)carbonyl)phenoxy)-3,3-diethyl-N-(1-(4-were)butyl)-4-oxo-1-azetidine the CSR-1-azetidinone;
(and) [S-(R*,S*)]-2-(4-((((2-dimethylamino)ethyl)ethylamino)carbonyl)phenoxy)-3,3-diethyl-N-(1-(4-were)butyl)-4-oxo-1-azetidinone;
(K) [S-(R*,S*)]-2-(4-((((2-diethylamino)ethyl)ethylamino)carbonyl)phenoxy)-3,3-diethyl-N-(1-(4-were)butyl)-4-oxo-1-azetidinone;
(l) [S-(R*,S*)]-2-(4-(((4-(2-hydroxyethyl)piperazine-1-yl)carbonyl)phenoxy)-3,3-diethyl-N-(1-(4-were)butyl)-4-oxo-1-azetidinone;
(m) [S-(R*,S*)]-2-(4-(((4-(2-hydroxyethyl)piperazine-1-yl)carbonyl)phenoxy)-3,3-diethyl-N-(1-(3,4-methylenedioxyphenyl)butyl)-4-oxo-1-azetidinone; or
(n) [S-(R*,S*)]-2-(4-(((4-ethoxycarbonylmethyl)piperazine-1-yl)carbonyl)phenoxy)-3,3-diethyl-N-(1-(3,4-methylenedioxyphenyl)butyl)-4-oxo-1-azetidinone;
24. Connection on p. 2 representing:
(a) [S-(R*,S*)]-2-(4-((4-morpholinyl)carbonyl)phenoxy)-3,3-diethyl-N-(1-(4-were)butyl)-4-oxo-1-azetidinone or
(b) [S-(R*,S*)]-2-(4-((4-morpholinyl)carbonyl)phenoxy)-3,3-diethyl-N-(1-(3,4-methylenedioxyphenyl)butyl)-4-oxo-1-azetidinone;
25. Connection on p. 1 representing:
(a) [S-(R*,S*)]-2-(4-((((2-dimethylamino)ethyl)methylamino)carbonyl)phenoxy)-3,3-diethyl-N-(1-(4-were)butyl)-4-oxo-1-azetidinone;
(b) [S-(R*, S*)]-2-(4-(((4-methyl)piperazine-1-yl)carbonyl)phenoxy)-3,3-diethyl-N-(1,3-diethyl-N-(1-(3,4-methylenedioxyphenyl)butyl)-4-oxo-1-azetidinone;
(g) [S-(R*,S*)]-2-(4-(((4-cyclopropyl)piperazine-1-yl)carbonyl)phenoxy)-3,3-diethyl-N-(1-(4-were)butyl)-4-oxo-1-azetidinone;
(d) [S-(R*,S*)]-2-(4-(((4-cyclopropyl)piperazine-1-yl)carbonyl)phenoxy)-3,3-diethyl-N-(1-(3,4-methylenedioxyphenyl)butyl)-4-oxo-1-azetidinone;
(e) [S-(R*, S*)]-2-(4-((piperazine-1-yl)carbonyl)phenoxy)-3,3-diethyl-N-(1-(4-were)butyl)-4-oxo-1-azetidinone; or
(W) [S-(R*, S*)]-2-(4-((piperazine-1-yl)carbonyl)phenoxy)-3,3-diethyl-N-(1-(3,4-methylenedioxyphenyl)butyl)-4-oxo-1-azetidinone.26. Connection on p. 2, where R is a C1-3alkyl; R1- C1-3alkyl; M is ethyl, propyl, butyl, pentyl or hexyl; R2(a) hydrogen; (b) C1-6alkyl or C1-6alkoxy, or R3is hydrogen; or R2and R3together with the formation of methylenedioxy; each of R9, R10and R11chosen independently of one another from the group consisting of hydrogen, C1-4the alkyl and C1-3alkoxyl1-3of alkyl; R7and R8together with the nitrogen atom to which they are attached, form a mono - or disubstituted ring selected from the group comprising (1) piperidinyl; (2) piperazinil; (3) morpholinyl; (4) pyrrolidinyl; (5) peril; (6) imidazolyl; (7) triazolyl; (8) tetrazolyl; (9) the 1-3alkyl, benzyloxycarbonyl, panels1-3alkylaminocarbonyl, pyrrolidinyl, hydroxys1-3alkyl, C1-6alkoxy, C1-4allyloxycarbonyl and oxoprop.27. Connection on p. 26, where R is methyl or ethyl; R1is methyl or ethyl; M is ethyl, propyl, butyl; R2(a) hydrogen; (b) C1-3alkyl or C1-3alkoxy.28. Connection on p. 1 representing [S-(R*,S*)]-2-(4-((4-methylpiperazin-1-yl)carbonyl)phenoxy)-3,3-diethyl-N-(1-(3,4-methylenedioxyphenyl)butyl)-4-oxo-1-azetidinone or its pharmaceutically acceptable salt.29. The compound according to any one of paragraphs.1 - 28 active inhibitor of leukocyte elastase person.30. The pharmaceutical composition inhibiting the elastase of human leukocytes, comprising the active principle and a pharmaceutically acceptable carrier, characterized in that it contains as active principle an effective amount of the compounds under item 1 or 2.31. The pharmaceutical composition according to p. 30, wherein the active ingredient contains a connection on p. 28 or its salt.32. A method of treating diseases caused by excessive activity of elastase, by introducing the inhibitor into the body, different temp CLASS="ptx2">33. The method of obtaining compounds of General formula I under item 1, in which R is ethyl, R4group
< / BR>where Q, Y, R7and R8are specified in paragraph 1 values
characterized in that the compound of General formula
< / BR>process connection formulas
< / BR>where R1, R1, R2, R3, R7, R8, Ra, Rb, M, Q and Y are specified in paragraph 1.Priority points:
27.10.92 - PP.1 - 8, 11 - 13, 14 - 19, 21, 22, 26 - 27, 29 - 33;
17.12.92 - PP.9, 10, 23 - 25, 28.
