U.S. patent application number 14/087854 was filed with the patent office on 2014-03-13 for spirocyclic nitriles as protease inhibitors.
This patent application is currently assigned to Sanofi. The applicant listed for this patent is Sanofi. Invention is credited to Armin BAUER, Anna KOHLMANN, Manfred SCHUDOK, Michael WAGNER.
Application Number | 20140073662 14/087854 |
Document ID | / |
Family ID | 38445013 |
Filed Date | 2014-03-13 |
United States Patent
Application |
20140073662 |
Kind Code |
A1 |
SCHUDOK; Manfred ; et
al. |
March 13, 2014 |
Spirocyclic nitriles as protease inhibitors
Abstract
The invention relates to substituted carbo- and heterocyclic
spiro compounds of the formula Ia which inhibit thiol proteases, to
processes for their preparation and to the use thereof as
medicaments.
Inventors: |
SCHUDOK; Manfred; (Eppstein,
DE) ; WAGNER; Michael; (Kriftel, DE) ; BAUER;
Armin; (Sulzbach, DE) ; KOHLMANN; Anna;
(Winchester, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Sanofi |
Paris |
|
FR |
|
|
Assignee: |
Sanofi
Paris
FR
|
Family ID: |
38445013 |
Appl. No.: |
14/087854 |
Filed: |
November 22, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13248366 |
Sep 29, 2011 |
8609681 |
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14087854 |
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12277880 |
Nov 25, 2008 |
8039480 |
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13248366 |
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PCT/EP2007/004550 |
May 23, 2007 |
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12277880 |
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Current U.S.
Class: |
514/278 ;
514/452; 514/616; 546/16; 549/333; 564/152 |
Current CPC
Class: |
A61P 19/02 20180101;
A61P 25/16 20180101; A61P 17/06 20180101; C07D 491/10 20130101;
C07D 221/20 20130101; A61P 31/04 20180101; C07D 211/66 20130101;
C07D 231/54 20130101; A61P 15/00 20180101; A61P 35/00 20180101;
A61P 9/00 20180101; A61P 17/02 20180101; A61P 1/16 20180101; A61P
7/02 20180101; A61P 11/06 20180101; A61P 19/10 20180101; A61P 29/02
20180101; A61P 37/08 20180101; A61P 29/00 20180101; A61P 1/00
20180101; A61P 11/00 20180101; A61P 37/06 20180101; C07C 255/46
20130101; A61P 21/04 20180101; C07D 471/10 20130101; A61P 19/00
20180101; C07C 2601/02 20170501; C07D 317/72 20130101; A61P 1/04
20180101; A61P 25/04 20180101; A61P 37/00 20180101; C07D 295/26
20130101; A61P 25/00 20180101; A61P 25/14 20180101; A61P 43/00
20180101; A61P 1/18 20180101; A61P 9/10 20180101; A61P 37/02
20180101; A61P 21/00 20180101; A61P 33/06 20180101; A61P 19/08
20180101; A61P 31/12 20180101; A61P 3/06 20180101; A61P 13/12
20180101; A61P 25/28 20180101; C07D 295/215 20130101; A61P 35/02
20180101; A61P 35/04 20180101; C07D 213/26 20130101; C07D 263/52
20130101; C07D 319/14 20130101; A61P 3/14 20180101; A61P 31/18
20180101; A61P 5/14 20180101; A61P 17/00 20180101; C07C 233/63
20130101; A61P 3/10 20180101; A61P 13/10 20180101; A61P 25/08
20180101; A61P 1/02 20180101 |
Class at
Publication: |
514/278 ; 546/16;
549/333; 514/452; 564/152; 514/616 |
International
Class: |
C07D 319/14 20060101
C07D319/14; C07C 233/63 20060101 C07C233/63; C07D 221/20 20060101
C07D221/20 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 1, 2006 |
DE |
102006025630.1 |
Claims
1. A compound selected from the group consisting of:
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3-methylbutyl]-1,4-dioxaspiro[4.5-
]decane-8-carboxamide;
N-[1-(1-cyanocyclopropylcarbamoyl)cyclohexyl]-8-azaspiro[4.5]decane-8-car-
boxamide;
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-cyclohexylmethyl-8-azasp-
iro[4.5]decane-8-carboxamide;
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3-methylbutyl]spiro[2.3]hexane-1--
carboxamide; or a physiologically tolerated salt thereof.
2. A pharmaceutical composition comprising a therapeutically
effective amount of the compound of claim 1 or a physiologically
tolerated salt thereof and a pharmaceutically acceptable
carrier.
3. A method of treating a disease, condition or disorder selected
from abnormally elevated bone degradation, allergies, Alzheimer's
disease, amyloidosis, ARDS, arterial thrombosis, asthma, atheromas,
atherosclerosis, autoimmune disorders, bacterial infections,
bronchiolitis, cerebral hemorrhage, cerebrovascular ischemia,
Huntington's chorea, chronic inflammations, CIPD (chronic
inflammatory demyelinizing polyradiculoneuropathy),
Creutzfeldt-Jakob disease, Crohn's disease, diabetes, emphysema,
encephalomyelitis, endometriosis, inflammatory respiratory
disorders, inflammatory pancreatitis, epilepsy, disorders
characterized by enhanced angiogenesis, excessive respiratory
pathway elastolysis, tissue grafts, gingivitis, glomerulonephritis,
glucocorticoid-induced osteoporosis, Graves' disease,
Guillain-Barre syndrome, Hashimoto's thyroiditis, hepatitis, HIV
infection, Huntington's disease, hypercalcemia, IBD, immune
impairment, interstitial cystitis, bone fracture, bone loss,
cancers, lupus erythematosus, malaria, metachromic leukodystrophy,
metastasizing osteogenesis, metastatis, multiple sclerosis,
multiple myeloma, muscular dystrophy, myasthenia gravis,
neurodegenerative disorders, neuropathic pain, chronic or diabetic
neuropathy, post-therapeutic neuralgia, trigeminal neuralgia,
painful diabetic polyneuropathy, post-stroke pain, post-amputation
pain, myelopathic or radiculopathic pain, atypical facial pain and
causalgia-like syndromes, organ rejection in transplants,
osteoarthritis, osteogenesis imperfecta, osteoporosis, Paget's
disease, pancreatitis, Parkinson's disease, pemphigus vulgaris,
periodontitis, plaque rupture, Pneumocystis carinii, pneumonitis,
psoriasis, restenosis, rheumatoid arthritis, scleroderma, systemic
lupus erythematosus, brain trauma, spinal cord trauma, tumor cell
invasion, viral infections, tooth loss, breast cancer, intestinal
cancer, ovarian cancer, cervical cancer, skin cancer, brain tumor,
Kaposi's sarcoma, B- and T-cell leukemia, lung cancer, lymph node
cancer, pancreatic cancer, prostrate cancer and sarcomas; said
method comprising administering to a patient in need thereof a
therapeutically effective amount of a compound according to claim 1
or a physiologically tolerated salt thereof.
4. The method of claim 3, wherein the condition or disorder is
osteoarthritis.
5. The method of claim 3, wherein the condition or disorder is bone
loss.
Description
[0001] This application is a continuation of U.S. application Ser.
No. 13/248,366, filed Sep. 29, 2011, which is a divisional of U.S.
application Ser. No. 12/277,880, filed Nov. 25, 2008, which is a
continuation of International Application No. PCT/EP2007/004550,
filed May 23, 2007, which are incorporated herein by reference in
their entirety; and claims the benefit of priority of German Patent
Application No. 102006025630.1, filed Jun. 1, 2006.
[0002] The invention relates to substituted carbo- and heterocyclic
spiro compounds of the formula Ia which inhibit thiol proteases, to
processes for their preparation and to the use thereof as
medicaments.
[0003] Proteolytic enzymes, known as proteases and peptidases, are
very important enzymes which make up about 2% of the genes in the
human organism, pathogenic microorganisms and also other life
forms. Their particular significance is that they influence many
physiological processes by playing an important role in the
activation, synthesis or degradation of other proteins. This
inevitably gives rise to a crucial regulatory function starting at
conception, birth, growth, maturation, aging, diseases up to
death.
[0004] The balance of the different processes is of crucial
significance for the life and survival of the organism. When there
is an imbalance of protease-catalyzed processes as a result of
endogenous or exogenous factors such as genetic predisposition or
environmental factors, massive disruption can occur in the normal
development process, acute to serious chronic health disorders up
to and including life-threatening diseases.
[0005] Equally, proteases are essential and responsible in
replication and transmission processes of viral, bacterial and
other parasitic organisms which are responsible, for instance, for
infection disorders, and equally essential, of course, for all
further physiological and pathophysiological processes in the plant
and animal kingdom.
[0006] Caused by this general great significance for our health, a
multitude of protease inhibitors have already been developed, which
are on the market or in all stages of development: not only as
medicaments, but also as diagnostics, vaccines or food
supplements.
[0007] A distinction is drawn between 5 classes of proteolytic
enzymes, divided according to the catalytically active radicals
relevant for the enzymatic hydrolysis: aspartyl proteases, serine
proteases, cysteine proteases, metalloproteases and threonine
protreases. Inhibitors of all of these classes are the subject of
comprehensive studies in a wide field for the control of various
types of disorders. Several very effective protease inhibitors are
on the market, for example ACE inhibitors, HIV-1 protease
inhibitors, and also thrombin and elastase inhibitors, followed by
a large number of inhibitors in clinical phases. A summary can be
found, for instance, in Medicinal Chemistry, 2005, Vol. 1, No. 1,
p. 71-104.
[0008] Cysteine (thiol) proteases are divided into three main
classes: Papain-like, ICE-like (caspases) and Picornaviral
proteases. From the point of view of the mechanism, the hydrolysis
of the amide bond proceeds in a similar way to that in the case of
the class of the serine proteases, via an attack of the thiolate
anion at the carbonyl carbon and formation of a tetrahedral
transition state. The most prominent representatives of the papain
superfamily, as the largest and most significant group of the thiol
proteases, are the cathepsins which have a natural wide
distribution in various tissues and to which an important function
is attributed both in normal physiological and pathological
processes. Particular emphasis should be given to intracellular
protein degradation and remodeling processes. Accordingly,
significance is ascribed to cysteine cathepsins in the following
general disorder types: musculoskeletal disorders, particularly
bone degradation disorders, inflammatory disorders, particularly
arthritides, atherosclerotic disorders, emphysemas, dystrophies,
cancers, disorders of the periodontal apparatus, infectious
disorders (viral, parasitic and bacterial infections),
neurodegenerative disorders, disorders of the immune system,
ischemias, leukodystrophies, glomerulonephritis. According to the
nature of the proteases, the pathogenic properties are exerted
especially by three high-level mechanisms: the degradation of
(connective) tissue, which initiates many types of symptoms and
also further processes, the generation of pathogenic or bioactive
proteins and peptides which themselves exert their action directly
or in signal cascades, and antigen processing, for example the
presentation of antigenic peptides at the cell surface, which then
finally initiates an immune response.
[0009] Known representatives of the cysteine cathepsins are
particularly Cathepsin B, H, K, L, F, V, W, X, O, C and S (A. J.
Barrett; N. D. Rawlings; J. F. Woessner; ed.; Handbook of
Proteolytic Enzymes, 2nd. ed., 2004; Publisher: Elsevier,
London).
[0010] Cathepsin F was found for the first time in macrophages and
is involved in antigen processing. Caused by the occurrence in
stimulated lung macrophages, an important function in inflammatory
respiratory pathway disorders has been postulated.
[0011] Cathepsin L is involved in normal lysosomal proteolysis, but
also in various disease events such as melanoma metastatis.
[0012] Cathepsin S plays a key role in many processes which are of
significance in the context of antigen presentation and are thus
present to an enhanced degree in antigen-presenting cells. In this
regard, inhibitors of cathepsin S are possibly active agents in the
prevention, inhibition or treatment of immune or autoimmune
disorders. Moreover, cathepsin S is also secreted by several
antigen-presenting cells and thus plays a role in extracellular
matrix interactions which likewise have crucial significance in
many pathological processes. Emphasis is given here to various
(auto)immune and inflammatory disorders; particularly Alzheimer's
disease, Huntington's disease, juvenile diabetes, multiple
sclerosis, pemphigus vulgaris, Graves' disease, Myasthenia gravis,
systemic Lupus erythematosus, IBD, rheumatoid arthritis and
Hashimoto's thyroiditis, MS, ALS, allerigic disorders such as
asthma, allogenic immune responses such as rejection reactions in
organ transplants or tissue grafts. Moreover, cathepsin S is
connected with COPD (such as emphysema), bronchiolitis, excessive
respiratory pathway elastolysis in asthma and bronchitis,
pneumonitis, but also with cardiovascular disorders such as plaque
ruptures and atheromers, and also endometriosis and chronic
neuropathic pain. Cathepsin S is also connected with fibrillary
disorders, and inhibitors can thus possibly be used for the
treatment of systemic amyloidosis.
[0013] Increased levels of cathepsin B and corresponding
distributions are found in various tumors--a role in tumor invasion
and metastatis is thus ascribed to cathepsin B. Enhanced cathepsin
B activity is likewise found in rheumatoid arthritis,
osteoarthritis, acute pancreatitis, inflammatory respiratory
pathway disorders, Pneumocystis carinii and bone and joint
disorders. A significant increase in synovial cathepsin B levels
has been detected in osteoarthritis models. A review of
cytokine-independent overexpression and relevance for
osteoarthritis can be found in A. Baici et al., Seminars in
Arthritis and Rheumatism, 34, 6, Suppl. 2, 24-28 (2005).
[0014] Cathepsin K expression is particularly marked (but not
exclusively) in osteoclasts (for example D. Bromme et al., J. Biol.
Chem. 271, 2126-32 (1996)) and represents about 98% of the total
cysteine protease activity there, mainly localized intracellularly
within the lysosome. An autosomal recessive disruption of cathepsin
K expression (absence through mutation), pycnodysostosis, is
characterized by an osteopetrotic phenotype, with reduced bone
resorption, ossification disorders and massive growth disorders. It
has likewise been possible to show with cathepsin K antisense
nucleotides and knockout mice that cathepsin K is responsible for
osteoclast-mediated bone degradation. It is therefore assumed that
inhibition of cathepsin K leads to reduced bone resorption and
should thus constitute a possible therapy for all disorders which
are characterized by elevated bone degradation, i.e. particularly
for the treatment of osteoporosis. Caused by a significantly
increased activity in the slightly acidic range between pH 4 and 8,
enzymatic degradation of the collagen network in bone proceeds
accompanied by acidolytic destruction of the mineral matrix. Here,
particularly human collagen type I is affected as a main
constituent of the protease in bone; this has been proven to be a
very good substrate for cathepsin K. Therefore, other disorders
which are accompanied by increased catabolic activity at the
collagen level are also connected with cathepsins and particularly
with cathepsin K. Foremost among these is osteoarthritis,
characterized by an imbalance of cartilage matrix buildup and
degradation, caused by catabolically active enzymes, for example
metalloproteinases, among others. It is therefore obvious and has
now also been proved that an inhibition of cathepsin K might
likewise have favorable effects here on the disease process
(synovial fibroblast-mediated collagen degradation by cathepsin K
is described in W.-S. Hou et al., Am. J. Pathol. 159, 2167-2177
(2001)). The significance of cathepsins K and S in musculoskeletal
disorders such as osteoporosis and osteoarthritis is described in
detail by D. Bromme et al., Advanced Drug Delivery Reviews 57,
973-993 (2005).
[0015] Caused by the above-described detailed findings concerning
cysteine cathepsins in various disease processes, they are
considered to be very promising points of attack in drug
development, such that an intensive search has commenced for
specific, group-specific or even unspecific inhibitors.
[0016] Inhibitors of cysteine proteases have been known for
sometime, for example cystatines as endogenous polypeptide
inhibitors. Low molecular weight inhibitors were isolated from
aspergillus for the first time in 1981. These are potent
irreversible inhibitors with low toxicity, but also inadequate
specificity, since not only cathepsins B, K, L, S and H but also
calpaines are widely inhibited. Since then, a multitude of
inhibitors with different specificities or mechanisms has been
found--therefore, both irreversibly covalently binding and
reversibly covalently binding or reversibly noncovalently binding
inhibitors have been found or synthesized. More recent developments
have been described in detail (W. Kim, K. Kang, Expert Opin. Ther.
Patents 13, 3, 419-32 (2002); U. B. Grabowska, Curr. Opin. Drug
Disc Dev. 8, 5, 619-30 (2005); R. L. Thurmond et al., Curr. Opin.
Invest. Drugs 6, 5, 473-482 (2005)).
[0017] Reversibly covalently binding inhibitors are of particular
interest. From this group, particularly the class of the nitriles
has been identified as very promising. These are described in
detail, for example in the applications WO99/24460, WO2000/55125,
WO2004/052921 and also in WO2005/040142.
[0018] In the effort to find effective compounds for treating
disorders caused directly or indirectly by cysteine cathepsins, it
has now been found that the inventive spiro compounds, spirocyclic
nitriles, are strong inhibitors of the cysteine cathepsins,
particularly of cathepsin K and/or S, while other cysteine
proteases such as calpain are inhibited much more weakly, if at
all. Moreover, the inventive compounds have improved
bioavailability, which has also been shown already in vitro in
corresponding Caco permeability tests.
[0019] The invention therefore relates to a compound of the formula
I
##STR00001##
and/or all stereoisomeric forms of the compound of the formula I
and/or mixtures of these forms in any ratio, and/or a
physiologically tolerated salt of the compound of the formula I,
and/or solvates or hydrates of the compound of the formula I,
and/or prodrugs of the compound of the formula I, where the
##STR00002##
radical is a spiro compound, [0020] in which the sub-rings
##STR00003##
[0020] are in each case the same or different and are each
independently [0021] a) a saturated or partly saturated
--(C.sub.3-C.sub.11)-cycloalkyl, in which cycloalkyl is unbridged,
bridged or fused and is unsubstituted or independently, according
to the ring size, mono-, di-, tri, tetra- or pentasubstituted by
R4, or [0022] b) a saturated or partly saturated, three- to
eleven-membered heterocycle which, according to the ring size, may
contain one, two, three or four identical or different heteroatoms
from the group of oxygen, nitrogen or sulfur, and in which the
heterocycle is unbridged, bridged or fused and is unsubstituted or
independently, according to the ring size, mono-, di-, tri-, tetra-
or pentasubstituted by R4, where [0023] R4 is --NO.sub.2, --CN,
.dbd.O, .dbd.S, --OH, --CF.sub.3, --SF.sub.5,
--(C.sub.0-C.sub.3)-alkylene-S--R10, --Si--(CH.sub.3).sub.3,
--O--CF.sub.3, --(C.sub.0-C.sub.3)-alkylene-C(O)--N(R21)-R22,
--(C.sub.0-C.sub.3)-alkylene-C(O)--R10,
--(C.sub.0-C.sub.3)-alkylene-C(O)--O--R10,
--(C.sub.0-C.sub.3)-alkylene-S(O)--R10, --S--CF.sub.3,
--(C.sub.0-C.sub.3)-alkylene-S(O).sub.2--R10,
--(C.sub.0-C.sub.5)-alkylene-S(O).sub.2--N(R21)-R22,
--(C.sub.0-C.sub.3)-alkylene-O--R10,
--(C.sub.0-C.sub.3)-alkylene-N(R21)-R22,
--(C.sub.0-C.sub.3)-alkylene-N(R10)-S(O).sub.2--R10,
--(C.sub.0-C.sub.5)-alkylene-(C.sub.1-C.sub.3)-fluoroalkyl,
--(C.sub.0-C.sub.5)-alkylene-(C.sub.3-C.sub.8)-cycloalkyl-R23,
--(C.sub.0-C.sub.5)-alkylene-N(R10)-C(O)--R21,
--(C.sub.0-C.sub.5)-alkylene-N(R10)-C(O)--N(R10)-R21,
--(C.sub.0-C.sub.5)-alkylene-O--C(O)--R21,
--(C.sub.0-C.sub.5)-alkylene-O--C(O)--O--R21,
--(C.sub.0-C.sub.5)-alkylene-NH--C(O)--O--R21,
--(C.sub.0-C.sub.5)-alkylene-O--C(O)--N(R10)-R21,
--(C.sub.0-C.sub.4)-alkyl, where alkyl is unsubstituted or mono-,
di- or trisubstituted independently by R9,
--(C.sub.0-C.sub.4)-alkylene-aryl, where aryl is selected from the
group of phenyl, indanyl, indenyl, naphthyl,
1,2,3,4-tetrahydronaphthyl, biphenylyl, 2-biphenylyl, 3-biphenylyl,
4-biphenylyl, anthryl or fluoroenyl, where aryl is unsubstituted or
mono-, di- or trisubstituted independently by R8, or
--(C.sub.0-C.sub.4)-alkylene-Het, where Het is selected from the
group of acridinyl, azepinyl, azetidinyl, aziridinyl,
benzimidazolinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,
benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,
benztetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl,
4aH-carbazolyl, carbolinyl, quinazolinyl, quinolinyl,
4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl,
cinnolinyl, deca-hydroquinolinyl, dibenzofuranyl,
dibenzothiophenyl, dihydrofuran[2,3-b]-tetrahydrofuranyl,
dihydrofuranyl, dioxolyl, dioxanyl, 2H, 6H-1,5,2-dithiazinyl,
furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,
1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,
isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,
isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolidinyl,
2-isothiazolinyl, isothiazolyl, isoxazolyl, isoxazolidinyl,
2-isoxazolinyl, morpholinyl, naphthyridinyl,
octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,
oxazolidinyl, oxazolyl, oxazolidinyl, oxothiolanyl, pyrimidinyl,
phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,
phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,
piperidinyl, pteridinyl, purynyl, pyranyl, pyrazinyl,
pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl,
pryidooxazolyl, pyridoimidazolyl, pyridothiazolyl,
pyridothiophenyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl,
pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyridinyl,
6H-1,2,5-thiadazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,
thienyl, thienoimidazolyl, thienooxazolyl, thienopyridine,
thienothiazolyl, thiomorpholinyl, thiophenyl, triazinyl,
1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl
and xanthenyl, and this Het radical is unsubstituted or
independently mono-, di- or trisubstituted by R8, or two adjacent
R4, together with the ring atoms to which they are bonded, form a
four- to eight-membered heterocycle or phenyl which, together with
the sub-ring to which the heterocycle or the phenyl is fused, forms
a bicyclic system, [0024] R8 is halogen, carbamimidoyl, --NO.sub.2,
.dbd.O, --CF.sub.3, --SF.sub.5, --C(O)--O--R10, --CN,
--C(O)--NH.sub.2, --OH, --NH.sub.2, --O--CF.sub.3, --S--CF.sub.3,
--C(O)--N(R10)-R20, --N(R10)-R20, --(C.sub.1-C.sub.8)-alkyl, where
alkyl is unsubstituted or mono-, di- or trisubstituted
independently by fluorine, chlorine, bromine, iodine, --NH.sub.2,
--OH, methoxy radical, --SO.sub.2--CH.sub.3, SO.sub.2--NH.sub.2 or
--SO.sub.2--CF.sub.3 or is mono- to decasubstituted by fluorine,
--O--(C.sub.1-C.sub.8)-alkyl, where alkyl is unsubstituted or
mono-, di- or trisubstituted independently by fluorine, chlorine,
bromine, iodine, NH.sub.2, --OH, methoxy radical,
--SO.sub.2--CH.sub.3 or --SO.sub.2--CF.sub.3 or is mono- to
decasubstituted by fluorine, [0025] --S--(C.sub.1-C.sub.8)-alkyl,
where alkyl is unsubstituted or mono-, di- or trisubstituted
independently by fluorine, chlorine, bromine, iodine, NH.sub.2,
--OH, methoxy radical, --SO.sub.2--CH.sub.3 or --SO.sub.2--CF.sub.3
or is mono- to decasubstituted by fluorine,
--(C.sub.0-C.sub.4)-alkylene-(C.sub.3-C.sub.8)-cycloalkyl or
--O--(C.sub.0-C.sub.4)-alkylene-(C.sub.3-C.sub.8)-cycloalkyl,
[0026] R9 is a halogen, --NO.sub.2, --CN, .dbd.O, .dbd.S, --OH,
--CF.sub.3, --SF.sub.S, --C(O)--O--R10, --N(R21)-R22,
--C(O)--N(R21)-R22, --(C.sub.0-C.sub.3)-alkylene-O--R10,
--(C.sub.0-C.sub.3)-alkylene-S--R10, --S--R10,
--Si--(CH.sub.3).sub.3, --N(R10)-S(O).sub.u--R10, where u is the
integer 1 or 2, --SO.sub.rR10, where r is the integer 1 or 2,
--S(O).sub.v--N(R10)-R20, where v is the integer 1 or 2, [0027]
--C(O)--R10, --(C.sub.1-C.sub.8)-alkyl, --O--R19,
--(C.sub.1-C.sub.8)-alkoxy, phenyl, phenyloxy-,
--(C.sub.1-C.sub.3)-fluoroalkyl, --NH--C(O)--NH--R21,
--O--C(O)--R10, --(C.sub.0-C.sub.4)-alkyl-C(O)--O--C(R19,
R11)-O--C(O)--R12, --O--CF.sub.3,
--(C.sub.0-C.sub.4)-alkyl-C(O)--O--C(R19, R11)-O--C(O)--O--R12,
--O--C(O)--N--R10, --N(R21)-C(O)--R22, --NH--C(O)--O--R10,
--S--CF.sub.3, Het, where Het is unsubstituted or mono-, di- or
trisubstituted independently by R8, or is a radical from the
following list
[0027] ##STR00004## [0028] where Me is methyl [0029] R10 and R20
are the same or different and are each independently a hydrogen
atom, --(C.sub.1-C.sub.6)-alkyl, [0030]
--(C.sub.0-C.sub.4)-alkyl-O--(C.sub.0-C.sub.4)-alkyl,
--(C.sub.1-C.sub.3)-fluoroalkyl,
--(C.sub.0-C.sub.5)-alkyl-(C.sub.3-C.sub.8)-cycloalkyl, [0031]
--(C.sub.0-C.sub.2)-alkylene-aryl, where aryl is as defined above
and is unsubstituted or mono-, di- or trisubstituted independently
by --(C.sub.1-C.sub.6)-alkyl, --O--(C.sub.1-C.sub.6)-alkyl, halogen
or --(C.sub.3-C.sub.8)-cycloalkyl, or [0032]
--(C.sub.0-C.sub.2)-alkylene-Het, where Het is as defined above and
is unsubstituted or mono-, di- or trisubstituted independently by
--(C.sub.1-C.sub.6)-alkyl, --O--(C.sub.1-C.sub.6)-alkyl, halogen or
--(C.sub.3-C.sub.8)-cycloalkyl, [0033] R19 and R11 are the same or
different and are each independently a hydrogen atom or
--(C.sub.1-C.sub.6)-alkyl, or [0034] R19 and R11, together with the
carbon atom to which they are bonded, form a three- to six-membered
cycloalkyl ring which is unsubstituted or mono-, di- or
trisubstituted independently by R10, [0035] R12 is
--(C.sub.1-C.sub.6)-alkyl, --(C.sub.1-C.sub.6)-alkyl-OH,
--(C.sub.1-C.sub.6)-alkyl-O--(C.sub.1-C.sub.6)-alkyl,
--(C.sub.3-C.sub.8)-cycloalkyl,
--(C.sub.1-C.sub.6)-alkyl-O--(C.sub.1-C.sub.8)-alkyl-(C.sub.3-C.sub.8)-cy-
cloalkyl, --(C.sub.1-C.sub.6)-alkyl-(C.sub.3-C.sub.8)-cycloalkyl
where the cycloalkyl radical is unsubstituted or mono-, di- or
trisubstituted independently by --OH, --O--(C.sub.1-C.sub.4)-alkyl
or R10, [0036] R21 and R22 are the same or different and are each
independently [0037] a hydrogen atom, --(C.sub.1-C.sub.6)-alkyl
where alkyl is unsubstituted or mono-, di- or trisubstituted
independently by R8, [0038]
--(C.sub.0-C.sub.6)-alkylene-(C.sub.3-C.sub.8)-cycloalkyl,
--SO.sub.t--R10 where t is the integer 1 or 2,
--(C.sub.1-C.sub.3)-fluoroalkyl, --O--R12, --S--R12, [0039]
--(C.sub.0-C.sub.6)-alkylene-aryl where aryl is as defined above
and alkylene and aryl are each unsubstituted or mono-, di- or
trisubstituted independently by R8 or [0040]
--(C.sub.0-C.sub.6)-alkylene-Het where Het is as defined above and
alkylene and Het are each unsubstituted or mono-, di- or
trisubstituted independently by R8, [0041] R21 and R22, together
with the nitrogen atom to which they are bonded, form a four- to
eight-membered monocyclic heterocyclic ring which, as well as the
nitrogen atom, may additionally contain, according to the ring
size, one or two identical or different heteroatoms from the group
of oxygen, nitrogen and sulfur, and in which the heterocyclic ring
is unsubstituted or mono-, di- or trisubstituted independently by
R8, [0042] R23 is a hydrogen atom, --OH or
--O--(C.sub.1-C.sub.4)-alkyl, [0043] X is a covalent bond,
--N(R7)-, --O--, --S-- or --(C(R13)(R14)).sub.n-- where n is the
integer 1, 2 or 3, [0044] R7 is a hydrogen atom,
--(C.sub.0-C.sub.4)-alkylene-(C.sub.3-C.sub.6)-cycloalkyl or
--(C.sub.1-C.sub.6)-alkyl, [0045] R13 and R14 are the same or
different and are each independently a hydrogen atom,
--(C.sub.0-C.sub.4)-alkylene-(C.sub.3-C.sub.6)-cycloalkyl,
--(C.sub.1-C.sub.3)-fluoroalkyl or --(C.sub.1-C.sub.4)-alkyl,
[0046] R13 and R14, together with the carbon atom to which they are
bonded, form a three- to six-membered cycloalkyl ring which is
unsubstituted or mono-, di- or trisubstituted independently by R10,
[0047] Y is a covalent bond, --C(O)--, --S(O)--, --S(O.sub.2)--,
--C(NR1)-, --C(S)--, --C(.dbd.N--CN)--, --C(.dbd.CHNO.sub.2)-- or
--CH(CF.sub.3)--, [0048] R1 is a hydrogen atom,
--(C.sub.1-C.sub.4)-alkyl or
--(C.sub.0-C.sub.4)-alkylene-(C.sub.3-C.sub.6)-cycloalkyl, [0049]
R2 and R3 are the same or different and are each independently a
hydrogen atom, --(C.sub.1-C.sub.10)-alkyl,
--(C.sub.0-C.sub.4)-alkylene-(C.sub.3-C.sub.8)-cycloalkyl,
--(C.sub.1-C.sub.6)-fluoroalkyl, --(C.sub.0-C.sub.4)-alkylene-aryl,
where aryl is unsubstituted or mono-, di- or trisubstituted
independently by R8, --(C.sub.0-C.sub.4)-alkylene-Het where Het is
unsubstituted or mono-, di- or trisubstituted independently by R8,
--(C.sub.1-C.sub.4)-alkylene-R15-R16 or
--(C.sub.0-C.sub.4)-alkylene-C(R27)(R28)(R29), [0050] R27 is a
hydrogen atom, halogen, --(C.sub.1-C.sub.9)-alkyl,
--(C.sub.1-C.sub.3)-fluoroalkyl,
--(C.sub.0-C.sub.4)-alkylene-(C.sub.3-C.sub.6)-cycloalkyl,
--(C.sub.0-C.sub.4)-alkylene-aryl, where aryl is unsubstituted or
mono-, di- or trisubstituted independently by R8,
--(C.sub.0-C.sub.4)-alkylene-Het where Het is unsubstituted or
mono-, di- or trisubstituted independently by R8, or
--(C.sub.0-C.sub.4)-alkylene-R15-R16, [0051] R28 and R29 are the
same or different and are each independently a hydrogen atom,
--(C.sub.1-C.sub.4)-alkyl or halogen, [0052] R15 is --N(R17)-,
--O--, --S--, --S(O)--, --S(O.sub.2)--, --C(O)--, --C(O)--O--,
--O--C(O)--, --O--C(O)--O--, --N(R17)-C(O)--, --C(O)--N(R17)-,
--S(O.sub.2)--N(R17)-, --S(O)--N(R17)-, --N(R17)-S(O.sub.2)--,
--N(R17)-C(O)--O--, --O--C(O)--N(R17)-, --N(R17)-C(O)--N(R18)-,
--N(R17)-C(N(R17))-N(R18)-, --N(R17)-C(N(R17))- or
--N(R17)-S(O.sub.2)--N(R18)-, where [0053] R17 and R18 are the same
or different and are each independently a hydrogen atom or
--(C.sub.1-C.sub.6)-alkyl, [0054] R16 is a hydrogen atom,
--(C.sub.1-C.sub.6)-alkyl,
--(C.sub.0-C.sub.4)-alkylene-(C.sub.3-C.sub.6)-cycloalkyl,
--(C.sub.1-C.sub.3)-fluoroalkyl, --(C.sub.0-C.sub.4)-alkylene-aryl,
where aryl is unsubstituted or mono-, di- or trisubstituted
independently by R8, [0055] --(C.sub.0-C.sub.4)-alkylene-Het where
Het is unsubstituted or mono-, di- or trisubstituted independently
by R8, [0056] R2 and R3, together with the carbon atom to which
they are bonded, form a three- to six-membered cycloalkyl ring
which is unsubstituted or mono-, di- or trisubstituted
independently by R8, or [0057] R2 and R3, together with the carbon
atom to which they are bonded, form a three- to six-membered
heterocycloalkyl radical which is unsubstituted or mono-, di- or
trisubstituted independently by R10, and [0058] Z is the
--N(R26)-(C(R24)(R25)).sub.m-CN radical where [0059] R26 is a
hydrogen atom, --(C.sub.1-C.sub.4)-alkyl or [0060]
--(C.sub.0-C.sub.4)-alkylene-(C.sub.3-C.sub.6)-cycloalkyl, [0061]
R24 and R25 are the same or different and are each independently a
hydrogen atom, --(C.sub.1-C.sub.6)-alkyl,
--(C.sub.0-C.sub.4)-alkylene-(C.sub.3-C.sub.6)-cycloalkyl, [0062]
--(C.sub.1-C.sub.3)-fluoroalkyl,
--(C.sub.1-C.sub.4)-alkylene-R15-R16,
--(C.sub.0-C.sub.4)-alkylene-aryl, where aryl is unsubstituted or
mono-, di- or trisubstituted independently by R8,
--(C.sub.0-C.sub.4)-alkylene-Het where Het is unsubstituted or
mono-, di- or trisubstituted independently by R8, and m is the
integer 1, 2 or 3, [0063] R24 and R25, together with the carbon
atom to which they are bonded, form a three- to six-membered
cycloalkyl ring which is unsubstituted or mono-, di- or
trisubstituted independently by R10 or fluorine, or [0064] R24 and
R25, together with the carbon atom to which they are bonded, form a
three- to six-membered heterocycloalkyl radical which is
unsubstituted or mono-, di- or trisubstituted independently by R10
or fluorine.
[0065] 2) The invention further provides the compound of the
formula I where the sub-ring
##STR00005##
has been selected from the following group
##STR00006## ##STR00007## ##STR00008## ##STR00009##
where the dotted lines indicate the particular point of attachment
to the second sub-ring, single bonds in the structures listed may
be replaced partly by double bonds, or further ring systems may be
fused on, and in which the sub-ring
##STR00010##
has been selected from the following group
##STR00011## ##STR00012##
where the dotted lines indicate the particular point of attachment
to the second sub-ring, single bonds in the structures listed may
be replaced partly by double bonds, and the two sub-rings A and B
are unsubstituted or independently mono- to tetrasubstituted by R4,
and the X, Y, R1, R2, R3, R4 and Z radicals are each as defined
above.
[0066] 3) The invention further provides the compound of the
formula I where the sub-rings
##STR00013##
have in each case been selected from cyclopropane cyclobutane,
cyclopentane, cyclohexane, cycloheptane, cyclooctane,
bicyclo[4.2.0]octane, octahydroindene, decalin,
decahydrobenzocycloheptene, dodecahydroheptalene,
bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[3.3.0]octane,
bicyclo[2.2.2]octane, spiro[2.5]octane, spiro[3.4]octane, azepane,
azepine, azetidine, aziridine, azirine, azocane, benzimidazoline,
2,3-dihydrobenzo[b]thiophene, 1,3-dihydrobenzo[c]thiophene,
2,3-dihydrobenzofuran, 2,3-dihydrobenzooxazole,
2,3-dihydrobenzothiazole, 1,3-dihydroisobenzofuran,
4,5-di-hydroisothiazole, 2,3-dihydroisoxazole,
2,5-dihydroisoxazole, 4,5-dihydroisoxazole,
5,6-dihydro-4H-[1,2]oxazine, benzo[1,3]dioxole, 1,4-diazepane,
1,2-diazepine, 1,3-diaze-pine, 1,4-diazepine, diaziridine,
diazirine, 1,4-diazocane, dioxane, 1,3-dioxane, dioxazine,
[1,3]dioxepane, 1,4-diozocane, dioxole, dioxolane, 1,3-dioxolane,
1,3-di-oxolene, [1,3]dithiane, [1,3]dithiolane,
hexahydropyridazine, hexahydropyrimidine, imidazoline,
imidazolidine, indane, indoline, isoindoline, isothiazolidine,
isothiazoline, isoxazoline, isoxazolidine, 2-isoxazoline,
morpholine, [1,3,4]oxadiazinane, [1,3,5]oxadiazinane,
[1,2,3]oxadiazolidine, [1,3,4]oxadiazolidine, 1,2-oxathiepane,
1,2-oxathiolane, [1,3]oxathiolane, 1,4-oxazepane, 1,2-oxazine,
1,3-oxazine, 1,4-oxazine, oxazinane, 1,3-oxazinane, oxazocane,
oxaziridine, oxazolidine, oxepane, oxetane, oxirane, oxocane,
piperazine, piperidine, pyran, pyrazoline, pyrazolidine,
pyrrolidine, pyrrolidinone, pyrroline, tetrahydroquinoline,
tetrahydrofuran, tetrahydroisoquinoline,
1,2,3,4-tetrahydronaphthalene, tetrahydropyran, tetrahydropyridine,
1,2,3,4-tetrahydro-pyrimidine, 1,2,5,6-tetrahydropyrimidine,
tetrahydrothiophene, tetrazine, thiadiazine, [1,2,6]thiadiazinane,
[1,3,4]thiadiazolidine, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine,
[1,2]thiazinane, [1,3]thiazinane, thiazolidine, thiazoline,
thiepane, thietane, thiomorpholine, thiopyran, 1,2,3-triazine,
1,2,4-triazine, 1,3,5-triazine, [1,2,4]triazinane or
[1,2,4]triazolidine, and in which the two sub-rings are each
unsubstituted or independently, according to the ring size, mono-,
di-, tri-, tetra- or pentasubstituted by R4, where [0067] R4 is
--NO.sub.2, --CN, .dbd.O, .dbd.S, --OH, --CF.sub.3, --SF.sub.S,
--(C.sub.0-C.sub.3)-alkylene-S--R10, --Si--(CH.sub.3).sub.3,
--O--CF.sub.3, --(C.sub.0-C.sub.3)-alkylene-C(O)--N(R21)-R22,
--(C.sub.0-C.sub.3)-alkylene-C(O)--R10,
--(C.sub.0-C.sub.3)-alkylene-C(O)--O--R10,
--(C.sub.0-C.sub.3)-alkylene-S(O)--R10, --S--CF.sub.3,
--(C.sub.0-C.sub.3)-alkylene-S(O).sub.2--R10,
--(C.sub.0-C.sub.5)-alkylene-S(O).sub.2--N(R21)-R22,
--(C.sub.0-C.sub.3)-alkylene-O--R10,
--(C.sub.0-C.sub.3)-alkylene-N(R21)-R22,
--(C.sub.0-C.sub.3)-alkylene-N(R10)-S(O).sub.2--R10,
--(C.sub.0-C.sub.5)-alkylene-(C.sub.1-C.sub.3)-fluoroalkyl,
--(C.sub.0-C.sub.5)-alkylene-(C.sub.3-C.sub.8)-cycloalkyl-R23,
--(C.sub.0-C.sub.5)-alkylene-N(R10)-C(O)--R21,
--(C.sub.0-C.sub.5)-alkylene-N(R10)-C(O)--N(R10)-R21,
--(C.sub.0-C.sub.5)-alkylene-NH--C(O)--O--R21,
--(C.sub.0-C.sub.5)-alkylene-O--C(O)--N(R10)-R21,
--(C.sub.0-C.sub.4)-alkyl, where alkyl is unsubstituted or mono-,
di- or trisubstituted independently by R9,
--(C.sub.0-C.sub.4)-alkylene-aryl, where aryl is selected from the
group of phenyl, indanyl, indenyl, naphthyl, biphenylyl,
2-biphenylyl, 3-biphenylyl, 4-biphenylyl, anthryl or fluoroenyl,
where aryl is unsubstituted or mono-, di- or trisubstituted
independently by R8, or [0068] --(C.sub.0-C.sub.4)-alkylene-Het,
where Het is selected from the group of acridinyl, azepinyl,
azetidinyl, aziridinyl, benzimidazolinyl, benzimidazolyl,
benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,
benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,
benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl,
quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,
quinuclidinyl, chromanyl, chromenyl, cinnolinyl,
deca-hydroquinolinyl, dibenzofuranyl, dibenzothiophenyl,
dihydrofuran[2,3-b]-tetrahydrofuranyl, dihydrofuranyl, dioxolyl,
dioxanyl, 2H, 6H-1,5,2-dithiazinyl, furanyl, furazanyl,
imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl,
indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl,
isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl
(benzimidazolyl), isothiazolidinyl, 2-isothiazolinyl, isothiazolyl,
isoxazolyl, isoxazolidinyl, 2-isoxazolinyl, morpholinyl,
naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,
1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl,
oxothiolanyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,
phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl,
phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purynyl,
pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl,
pyridazinyl, pryidooxazolyl, pyridoimidazolyl, pyridothiazolyl,
pyridothiophenyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl,
pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyridinyl,
6H-1,2,5-thiadazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,
thienyl, thienoimidazolyl, thienooxazolyl, thienopyridine,
thienothiazolyl, thiomorpholinyl, thiophenyl, triazinyl,
1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl
and xanthenyl, and this Het radical is unsubstituted or
independently mono-, di- or trisubstituted by R8, [0069] R8 is
halogen, carbamimidoyl, --NO.sub.2, .dbd.O, --CF.sub.3, --SF.sub.S,
--C(O)--O--R10, --CN, --C(O)--NH.sub.2, --OH, --NH.sub.2,
--O--CF.sub.3, --C(O)--N(R10)-R20, --N(R10)-R20,
(C.sub.3-C.sub.8)-cycloalkyl, --O--(C.sub.1-C.sub.8)-alkyl,
--O--(C.sub.0-C.sub.4)-alkylene-(C.sub.3-C.sub.6)-cycloalkyl,
(C.sub.1-C.sub.8)-alkyl,
--(C.sub.0-C.sub.4)-alkylene-(C.sub.3-C.sub.8)-cycloalkyl, where
the alkyl radicals mentioned are each unsubstituted or mono-, di-
or trisubstituted independently by halogen, NH.sub.2, --OH,
--O--CH.sub.3, --SO.sub.2--CH.sub.3 or --SO.sub.2--CF.sub.3, [0070]
R9 is halogen, --NO.sub.2, --CN, .dbd.O, --OH, --CF.sub.3,
--C(O)--O--R10, --N(R21)-R22, --C(O)--N(R21)-R22,
--(C.sub.3-C.sub.8)-cycloalkyl,
--(C.sub.0-C.sub.3)-alkylene-O--R10, --Si--(CH.sub.3).sub.3,
--N(R10)-S(O).sub.u--R10 where u is the integer 1 or 2, --S--R10,
[0071] --SO.sub.rR10 where r is the integer 1 or 2,
--S(O).sub.v--N(R10)-R20 where v is the integer 1 or 2,
--C(O)--R10, --(C.sub.1-C.sub.8)-alkyl, --(C.sub.1-C.sub.8)-alkoxy,
phenyl, phenyloxy-, --(C.sub.1-C.sub.3)-fluoroalkyl, --O--R19,
--NH--C(O)--NH--R10, --(C.sub.0-C.sub.4)-alkyl-C(O)--O--C(R19,
R11)-O--C(O)--R12, --NH--C(O)--NH--R21, --N(R21)-C(O)--R22,
--(C.sub.0-C.sub.4)-alkyl-C(O)--O--C(R19, R11)-O--C(O)--O--R12,
--NH--C(O)--O--R10, --O--CF.sub.3, Het, where Het is as defined
above and is unsubstituted or mono-, di- or trisubstituted
independently by R8, or a radical from the following list
##STR00014##
[0071] where Me is methyl, [0072] R10 and R20 are the same or
different and are each independently a hydrogen atom,
--(C.sub.1-C.sub.6)-alkyl, --(C.sub.0-C.sub.4)-alkyl-OH,
--(C.sub.1-C.sub.3)-fluoroalkyl,
--(C.sub.0-C.sub.4)-alkyl-O--(C.sub.1-C.sub.4)-alkyl,
--(C.sub.0-C.sub.5)-alkyl-(C.sub.3-C.sub.8)-cycloalkyl,
--(C.sub.0-C.sub.2)-alkylene-aryl, where aryl is as defined above
and is unsubstituted or mono-, di- or trisubstituted independently
by --(C.sub.1-C.sub.6)-alkyl, --O--(C.sub.1-C.sub.6)-alkyl, halogen
or [0073] --(C.sub.3-C.sub.8)-cycloalkyl, or
--(C.sub.0-C.sub.2)-alkylene-Het where Het is as defined above and
is unsubstituted or mono-, di- or trisubstituted independently by
--(C.sub.1-C.sub.6)-alkyl, --O--(C.sub.1-C.sub.6)-alkyl, halogen or
--(C.sub.3-C.sub.8)-cycloalkyl, [0074] R19 and R11 are the same or
different and are each independently a hydrogen atom or
--(C.sub.1-C.sub.6)-alkyl, or [0075] R19 and R11, together with the
carbon atom to which they are bonded, form a three- to six-membered
cycloalkyl ring which is unsubstituted or mono-, di- or
trisubstituted independently by R10, [0076] R12 is
--(C.sub.1-C.sub.6)-alkyl, --(C.sub.1-C.sub.6)-alkyl-OH,
--(C.sub.1-C.sub.6)-alkyl-O--(C.sub.1-C.sub.6)-alkyl,
--(C.sub.3-C.sub.8)-cycloalkyl,
--(C.sub.1-C.sub.6)-alkyl-O--(C.sub.1-C.sub.8)-alkyl-(C.sub.3-C.sub.8)-cy-
cloalkyl, --(C.sub.1-C.sub.6)-alkyl-(C.sub.3-C.sub.8)-cycloalkyl,
where the cycloalkyl radical is unsubstituted or mono-, di- or
trisubstituted independently by --OH, --O--(C.sub.1-C.sub.4)-alkyl
or R10, [0077] R21 and R22 are the same or different and are each
independently a hydrogen atom, --(C.sub.1-C.sub.6)-alkyl, where
alkyl is unsubstituted or mono-, di- or trisubstituted
independently by R8, --O--R12,
--(C.sub.0-C.sub.6)-alkylene-(C.sub.3-C.sub.8)-cycloalkyl,
--SO.sub.t--R10, where t is the integer 1 or 2,
--(C.sub.1-C.sub.3)-fluoroalkyl, --(C.sub.0-C.sub.6)-alkylene-aryl
where aryl is as defined above and alkylene and aryl are
unsubstituted or mono-, di- or trisubstituted independently by R8,
or [0078] --(C.sub.0-C.sub.6)-alkylene-Het where Het is as defined
above and alkylene and Het are unsubstituted or mono-, di- or
trisubstituted independently by R8, [0079] R21 and R22, together
with the nitrogen atom to which they are bonded, form a four- to
eight-membered heterocyclic ring which, as well as the nitrogen
atom, may additionally contain, according to the ring size, one or
two identical or different heteroatoms from the group of oxygen,
nitrogen or sulfur, and in which the heterocycle is unsubstituted
or mono-, di- or trisubstituted independently by R8, [0080] R23 is
a hydrogen atom, --OH or --O--(C.sub.1-C.sub.4)-alkyl, [0081] X is
a covalent bond, --N(R7)- or --O--, where [0082] R7 is a hydrogen
atom, --(C.sub.0-C.sub.4)-alkylene-(C.sub.3-C.sub.6)-cycloalkyl or
--(C.sub.1-C.sub.4)-alkyl, [0083] Y is a covalent bond, --C(O)--,
--C(S)--, --C(.dbd.N--CN)--, --C(.dbd.CHNO.sub.2)-- or
--S(O.sub.2)--, [0084] R1 is a hydrogen atom, [0085] R2 and R3 are
the same or different and are each independently a hydrogen atom or
--(C.sub.0-C.sub.3)-alkylene-C(R27)(R28)(R29), [0086] R27 is a
hydrogen atom, halogen, --(C.sub.1-C.sub.9)-alkyl,
--(C.sub.1-C.sub.3)-fluoroalkyl,
--(C.sub.0-C.sub.4)-alkylene-(C.sub.3-C.sub.6)-cycloalkyl,
--(C.sub.0-C.sub.4)-alkylene-aryl where aryl is as defined above
and is unsubstituted or mono-, di- or trisubstituted independently
by R8, --(C.sub.0-C.sub.4)-alkylene-Het where Het is as defined
above and is unsubstituted or mono-, di- or trisubstituted
independently by R8, or --(C.sub.0-C.sub.4)-alkylene-R15-R16,
[0087] R28 and R29 are the same or different and are each
independently a hydrogen atom, --(C.sub.1-C.sub.4)-alkyl or
fluorine, [0088] R28 and R29, together with the carbon atom to
which they are bonded, form a --(C.sub.3-C.sub.6)-cycloalkyl,
[0089] R15 is --N(R17)-, --O--, --S--, --S(O)--, --S(O.sub.2)--,
--C(O)--, --C(O)--O--, --O--C(O)--, --N(R17)-C(O)--,
--C(O)--N(R17)-, --S(O.sub.2)--N(R17)-, --N(R17)-S(O.sub.2)--,
--N(R17)-C(O)--O--, --O--C(O)--N(R17)-, --N(R17)-C(O)--N(R18)- or
--N(R17)-S(O.sub.2)--N(R18)-, where [0090] R17 and R18 are the same
or different and are each independently a hydrogen atom or
--(C.sub.1-C.sub.6)-alkyl, [0091] R16 is a hydrogen atom,
--(C.sub.1-C.sub.6)-alkyl,
--(C.sub.0-C.sub.4)-alkylene-(C.sub.3-C.sub.6)-cycloalkyl,
--(C.sub.1-C.sub.3)-fluoroalkyl, --(C.sub.0-C.sub.4)-alkylene-aryl
where aryl is as defined above and is unsubstituted or mono-, di-
or trisubstituted independently by R8,
--(C.sub.0-C.sub.4)-alkylene-Het where Het is as defined above and
is unsubstituted or mono-, di- or trisubstituted independently by
R8, [0092] R2 and R3, together with the carbon atom to which they
are bonded, form a three- to six-membered cycloalkyl ring which is
unsubstituted or mono-, di- or trisubstituted independently by R8,
or [0093] R2 and R3, together with the carbon atom to which they
are bonded, form a three- to six-membered heterocycloalkyl radical
which is unsubstituted or mono-, di- or trisubstituted
independently by R10, and [0094] Z is the --N(R26)-C(R24)(R25)-CN
radical, where [0095] R26 is a hydrogen atom,
--(C.sub.1-C.sub.4)-alkyl or
--(C.sub.0-C.sub.4)-alkylene-(C.sub.3-C.sub.6)-cycloalkyl, [0096]
R24 and R25 are the same or different and are each independently a
hydrogen atom, --(C.sub.1-C.sub.6)-alkyl,
--(C.sub.0-C.sub.4)-alkylene-(C.sub.3-C.sub.6)-cycloalkyl,
--(C.sub.1-C.sub.3)-fluoroalkyl, --(C.sub.0-C.sub.4)-alkylene-aryl
where aryl is as defined above and is unsubstituted or mono-, di-
or trisubstituted independently by R8,
--(C.sub.0-C.sub.4)-alkylene-Het where Het is as defined above and
is unsubstituted or mono-, di- or trisubstituted by R8, or
--(C.sub.1-C.sub.4)-alkylene-R15-R16, or [0097] R24 and R25,
together with the carbon atom to which they are bonded, form a
three- to six-membered cycloalkyl ring which is unsubstituted or
mono-, di- or trisubstituted independently by R10 or fluorine,
[0098] R24 and R25, together with the carbon atom to which they are
bonded, form a three- to six-membered heterocycloalkyl radical
which is unsubstituted or mono-, di- or trisubstituted
independently by R10 or fluorine.
[0099] 4) The invention further provides the compound of the
formula Ia
##STR00015##
where the sub-rings
##STR00016##
are each selected from the abovementioned groups, and in which the
two sub-rings are each unsubstituted or independently, according to
the ring size, mono-, di-, tri-, tetra- or pentasubstituted by R4,
[0100] R4 is --NO.sub.2, --CN, .dbd.O, .dbd.S, --OH, --CF.sub.3,
--SF.sub.S, --(C.sub.0-C.sub.3)-alkylene-S--R10, O--CF.sub.3,
--Si--(CH.sub.3).sub.3, --O--CF.sub.3,
--(C.sub.0-C.sub.5)-alkylene-O--C(O)--R21,
--(C.sub.0-C.sub.5)-alkylene-C(O)-.beta.--R10,
--(C.sub.0-C.sub.3)-alkylene-O--R10,
--(C.sub.0-C.sub.3)-alkylene-N(R21)-R22,
--(C.sub.0-C.sub.3)-alkylene-N(R10)-S(O.sub.2)--R10,
--(C.sub.0-C.sub.5)-alkylene-(C.sub.3-C.sub.8)-cycloalkyl-R23,
--(C.sub.0-C.sub.5)-alkylene-(C.sub.1-C.sub.3)-fluoroalkyl,
--(C.sub.0-C.sub.5)-alkylene-N(R10)-C(O)--R21,
--(C.sub.0-C.sub.3)-alkylene-C(O)--N(R21)-R22,
--(C.sub.0-C.sub.4)-alkyl where alkyl is unsubstituted or mono-,
di- or trisubstituted independently by R9,
--(C.sub.0-C.sub.4)-alkylene-aryl where aryl is selected from the
group of phenyl, indanyl, indenyl, naphthyl, where aryl is
unsubstituted or mono-, di- or trisubstituted independently by R8,
or --(C.sub.0-C.sub.4)-alkylene-Het where Het is selected from the
group of azetidinyl, benzimidazolinyl, benzimidazolyl,
benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl,
benzisoxazolyl, benzisothiazolyl, quinolinyl, dioxolyl, dioxanyl,
furanyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl,
indolyl, 3H-indolyl, isoindolinyl, isoindolyl, isoquinolinyl,
isothiazolidinyl, 2-isothiazolinyl, isothiazolyl, isoxazolyl,
isoxazolidinyl, 2-isoxazolinyl, morpholinyl,
octahydroisoquinolinyl, oxazolyl, oxazolidinyl, pyrimidinyl,
piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolinyl,
pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl,
pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyridinyl,
thiazolyl, thienyl, thienopyridinyl, thiomorpholinyl, thiophenyl,
and this Het radical is unsubstituted or independently mono-, di-
or trisubstituted by R8, [0101] R8 is halogen, carbamimidoyl,
--NO.sub.2, .dbd.O, --CF.sub.3, --SF.sub.5, --C(O)--O--R10, --CN,
--C(O)--NH.sub.2, --OH, --NH.sub.2, --O--CF.sub.3,
--C(O)--N(R10)-R20, --N(R10)-R20, --(C.sub.3-C.sub.8)-cycloalkyl,
--O--(C.sub.1-C.sub.8)-alkyl,
--O--(C.sub.0-C.sub.4)-alkylene-(C.sub.3-C.sub.6)-cycloalkyl,
--(C.sub.1-C.sub.8)-alkyl,
--(C.sub.0-C.sub.4)-alkylene-(C.sub.3-C.sub.8)-cycloalkyl, where
the alkyl radicals mentioned are each unsubstituted or mono-, di-
or trisubstituted independently by halogen, NH.sub.2, --OH,
--O--CH.sub.3, --SO.sub.2--CH.sub.3 or --SO.sub.2--CF.sub.3, [0102]
R9 is halogen, --NO.sub.2, --CN, .dbd.O, --OH, --CF.sub.3,
--C(O)--O--R10, --C(O)--N(R21)-R22, --N(R21)-R22,
--(C.sub.3-C.sub.8)-cycloalkyl,
--(C.sub.0-C.sub.3)-alkylene-O--R10, --Si--(CH.sub.3).sub.3,
--N(R10)-S(O).sub.u--R10 where u is the integer 1 or 2, --S--R10,
--SO.sub.r--R10 where r is the integer 1 or 2,
--S(O).sub.v--N(R10)-R20 where v is the integer 1 or 2,
--C(O)--R10, --(C.sub.1-C.sub.8)-alkyl, --(C.sub.1-C.sub.8)-alkoxy,
phenyl, phenyloxy-, --(C.sub.1-C.sub.3)-fluoroalkyl, --O--R19,
--NH--C(O)--NH--R10, --(C.sub.0-C.sub.4)-alkyl-C(O)--O--C(R11,
R19)-O--C(O)--R12, --NH--C(O)--NH--R21, --N(R21)-C(O)--R22,
--(C.sub.0-C.sub.4)-alkyl-C(O)--O--C(R11, R19)-O--C(O)--O--R12,
--NH--C(O)--O--R10, --O--CF.sub.3 or Het where Het is as defined
above and is unsubstituted or mono-, di- or trisubstituted
independently by R8, [0103] R10 and R20 are the same or different
and are each independently a hydrogen atom,
--(C.sub.1-C.sub.6)-alkyl, --(C.sub.0-C.sub.4)-alkyl-OH,
--(C.sub.1-C.sub.3)-fluoroalkyl,
(C.sub.0-C.sub.4)-alkyl-O--(C.sub.1-C.sub.4)-alkyl,
--(C.sub.0-C.sub.5)-alkyl-(C.sub.3-C.sub.8)-cycloalkyl,
--(C.sub.0-C.sub.2)-alkylene-aryl where aryl is as defined above
and is unsubstituted or mono-, di- or trisubstituted independently
by --(C.sub.1-C.sub.6)-alkyl, --O--(C.sub.1-C.sub.6)-alkyl, halogen
or --(C.sub.3-C.sub.8)-cycloalkyl, or
--(C.sub.0-C.sub.2)-alkylene-Het where Het is as defined above and
is unsubstituted or mono-, di- or trisubstituted independently by
--(C.sub.1-C.sub.6)-alkyl, --O--(C.sub.1-C.sub.6)-alkyl, halogen or
--(C.sub.3-C.sub.8)-cycloalkyl, [0104] R11 and R19 are the same or
different and are each independently a hydrogen atom or
--(C.sub.1-C.sub.6)-alkyl, [0105] R12 is --(C.sub.1-C.sub.6)-alkyl,
--(C.sub.1-C.sub.6)-alkyl-OH,
--(C.sub.1-C.sub.6)-alkyl-O--(C.sub.1-C.sub.6)-alkyl,
--(C.sub.3-C.sub.8)-cycloalkyl,
--(C.sub.1-C.sub.6)-alkyl-O--(C.sub.1-C.sub.8)-alkyl-(C.sub.3-C.sub.8)-cy-
cloalkyl, --(C.sub.1-C.sub.6)-alkyl-(C.sub.3-C.sub.8)-cycloalkyl,
where the cycloalkyl radical is unsubstituted or mono-, di- or
trisubstituted independently by --OH, --O--(C.sub.1-C.sub.4)-alkyl
or R10, [0106] R21 and R22 are the same or different and are each
independently a hydrogen atom, --(C.sub.1-C.sub.6)-alkyl where
alkyl is unsubstituted or mono-, di- or trisubstituted
independently by R8,
--(C.sub.0-C.sub.6)-alkylene-(C.sub.3-C.sub.8)-cycloalkyl,
--SO.sub.t--R10 where t is the integer 1 or 2,
--(C.sub.1-C.sub.3)-fluoroalkyl, --O--R12,
--(C.sub.0-C.sub.6)-alkylene-aryl where aryl is as defined above
and alkylene and aryl are each unsubstituted or mono-, di- or
trisubstituted independently by R8 or
--(C.sub.0-C.sub.6)-alkylene-Het where Het is as defined above and
alkylene and Het are each unsubstituted or mono-, di- or
trisubstituted independently by R8, [0107] R21 and R22, together
with the nitrogen atom to which they are bonded, form a four- to
eight-membered monocyclic heterocyclic ring which, as well as the
nitrogen atom, additionally, according to the ring size, may
contain one or two identical or different heteroatoms from the
group of oxygen, nitrogen or sulfur and in which the heterocycle is
unsubstituted or mono-, di- or trisubstituted independently by R8,
[0108] R23 is a hydrogen atom, --OH or
--O--(C.sub.1-C.sub.4)-alkyl, [0109] X is a covalent bond, --N(R7)-
or --O--, where [0110] R7 is a hydrogen atom,
--(C.sub.0-C.sub.4)-alkylene-(C.sub.3-C.sub.6)-cycloalkyl or
--(C.sub.1-C.sub.4)-alkyl, [0111] Y is --C(O)--, --C(S)-- or
--S(O.sub.2)--, [0112] p is the integer 1 or 2, [0113] R27 is a
hydrogen atom, --(C.sub.1-C.sub.6)-alkyl,
--(C.sub.0-C.sub.4)-alkylene-(C.sub.3-C.sub.6)-cycloalkyl, halogen,
--(C.sub.0-C.sub.4)-alkylene-Het where Het is as defined above and
is unsubstituted or substituted by halogen,
--(C.sub.1-C.sub.6)-alkyl, --O--(C.sub.1-C.sub.3)-fluoroalkyl or
--O--(C.sub.1-C.sub.6)-alkyl, or
--(C.sub.0-C.sub.2)-alkylene-phenyl where phenyl is unsubstituted
or substituted by halogen, --(C.sub.1-C.sub.6)-alkyl,
--O--(C.sub.1-C.sub.3)-fluoroalkyl or --O--(C.sub.1-C.sub.6)-alkyl,
[0114] R26 is a hydrogen atom, --(C.sub.1-C.sub.4)-alkyl or
--(C.sub.0-C.sub.4)-alkylene-(C.sub.3-C.sub.6)-cycloalkyl, [0115]
R24 and R25 are the same or different and are each independently a
hydrogen atom, --(C.sub.1-C.sub.6)-alkyl,
--(C.sub.0-C.sub.4)-alkylene-(C.sub.3-C.sub.6)-cycloalkyl,
--(C.sub.1-C.sub.3)-fluoroalkyl, --(C.sub.0-C.sub.4)-alkylene-aryl
where aryl is as defined above and is unsubstituted or mono-, di-
or trisubstituted independently by R8, or
--(C.sub.0-C.sub.4)-alkylene-Het where Het is as defined above and
is unsubstituted or mono-, di- or trisubstituted independently by
R8, [0116] R24 and R25, together with the carbon atom to which they
are bonded, form a three- to six-membered cycloalkyl ring which is
unsubstituted or mono-, di- or trisubstituted independently by R10
or fluorine, [0117] R24 and R25, together with the carbon atom to
which they are bonded, form a three- to six-membered
heterocycloalkyl radical which is unsubstituted or mono-, di- or
trisubstituted independently by R10 or fluorine.
[0118] 5) The invention further provides the compound of the
formula Ia where the sub-rings
##STR00017##
have each been selected from cyclopropane, cyclobutane,
cyclopentane, cyclohexane, cycloheptane, cyclooctane,
bicyclo[4.2.0]octane, octahydroindene, decalin,
decahydrobenzocycloheptene, dodecahydroheptalene,
bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[3.3.0]octane,
bicyclo[2.2.2]octane, spiro[2.5]octane, spiro[3.4]octane, azepane,
azepine, azetidine, aziridine, azirine, azocane, benzimidazoline,
2,3-dihydrobenzo[b]thiophene, 1,3-dihydrobenzo[c]thiophene,
2,3-dihydrobenzofuran, 2,3-dihydrobenzooxazole,
2,3-dihydrobenzothiazole, 1,3-dihydroisobenzofuran,
4,5-dihydroisothiazole, 2,3-dihydroisoxazole, 2,5-dihydroisoxazole,
4,5-dihydroisoxazole, 5,6-dihydro-4H-[1,2]oxazine,
benzo[1,3]dioxole, 1,4-diazepane, 1,2-diazepine, 1,3-diazepine,
1,4-diazepine, diaziridine, diazirine, 1,4-diazocane, dioxane,
1,3-dioxane, dioxazine, [1,3]dioxepane, 1,4-diozocane, dioxole,
dioxolane, 1,3-dioxolane, 1,3-dioxolene, [1,3]dithiane,
[1,3]dithiolane, hexahydropyridazine, hexahydropyrimidine,
imidazoline, imidazolidine, indane, indoline, isoindoline,
isothiazolidine, isothiazoline, isoxazoline, isoxazolidine,
2-isoxazoline, morpholine, [1,3,4]oxadiazinane,
[1,3,5]oxadiazinane, [1,2,3]oxadiazolidine, [1,3,4]oxadiazolidine,
1,2-oxathiepane, 1,2-oxathiolane, [1,3]oxathiolane, 1,4-oxazepane,
1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazinane, 1,3-oxazinane,
oxazocane, oxaziridine, oxazolidine, oxepane, oxetane, oxirane,
oxocane, piperazine, piperidine, pyran, pyrazoline, pyrazolidine,
pyrrolidine, pyrrolidinone, pyrroline, tetrahydroquinoline,
tetrahydrofuran, tetrahydroisoquinoline,
1,2,3,4-tetrahydronaphthalene, tetrahydropyran, tetrahydropyridine,
1,2,3,4-tetrahydro-pyrimidine, 1,2,5,6-tetrahydropyrimidine,
tetrahydrothiophene, tetrazine, thiadiazine, [1,2,6]thiadiazinane,
[1,3,4]thiadiazolidine, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine,
[1,2]thiazinane, [1,3]thiazinane, thiazolidine, thiazoline,
thiepane, thietane, thiomorpholine, thiopyran, 1,2,3-triazine,
1,2,4-triazine, 1,3,5-triazine, [1,2,4]triazinane or
[1,2,4]triazolidine, and in which the two sub-rings are each
unsubstituted or independently, according to the ring size, mono-,
di-, tri-, tetra- or pentasubstituted by R4, and the X, Y, R27, p,
R26, R24, R25 and R4 radicals are each as defined under 4).
[0119] 6) The invention further provides the compound of the
formula Ia where the sub-rings
##STR00018##
are each independently selected from the group of azetidine,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
1,3-dihydroisobenzofuran, 2,3-dihydroisoxazole,
2,5-dihydroisoxazole, 4,5-dihydroisoxazole, 1,3-dioxane, dioxolane,
1,3-dioxolane, imidazolidine, indane, morpholine, 1,3-oxazinane,
oxazolidine, piperazine, piperidine, pyrrolidine, tetrahydrofuran,
and 1,2,3,4-tetrahydronaphthalene, and in which the two sub-rings
are each unsubstituted or independently, according to the ring
size, mono-, di- or trisubstituted by R4, [0120] R4 is .dbd.O,
.dbd.S, --(C.sub.0-C.sub.3)-alkylene-C(O)--O--R10,
--(C.sub.0-C.sub.3)-alkylene-N(R21)-R22,
--(C.sub.0-C.sub.3)-alkylene-NH--C(O)--R21,
--(C.sub.0-C.sub.4)-alkylene-(C.sub.3-C.sub.6)-cycloalkyl-R23,
--(C.sub.0-C.sub.3)-alkylene-O--R10,
--(C.sub.0-C.sub.4)-alkylene-phenyl, where phenyl is unsubstituted
or mono-, di- or trisubstituted independently by R8, or
--(C.sub.0-C.sub.4)-alkyl where alkyl is unsubstituted or mono-,
di- or trisubstituted independently by R9, [0121] R8 is fluorine,
chlorine, bromine, --O--(C.sub.1-C.sub.3)-fluoroalkyl or
--O--(C.sub.1-C.sub.4)-alkyl, [0122] R9 is halogen, --NO.sub.2,
--CN, .dbd.O, --OH, --CF.sub.3, --C(O)--O--R10, --C(O)--N(R21)-R22,
--N(R21)-R22, --(C.sub.3-C.sub.8)-cycloalkyl,
--(C.sub.0-C.sub.3)-alkylene-O--R10, --Si--(CH.sub.3).sub.3,
--N(R10)-S(O).sub.u--R10 where u is the integer 1 or 2, --S--R10,
--SO.sub.r--R10 where r is the integer 1 or 2,
--S(O).sub.v--N(R10)-R20 where v is the integer 1 or 2,
--C(O)--R10, --(C.sub.1-C.sub.8)-alkyl, --(C.sub.1-C.sub.8)-alkoxy,
phenyl, phenyloxy-, --(C.sub.1-C.sub.3)-fluoroalkyl, --O--R19,
--NH--C(O)--NH--R10,
--(C.sub.0-C.sub.4)-alkyl-C(O)--O--C(R11,R19)-O--C(O)--R12,
--NH--C(O)--NH--R21, --N(R21)-C(O)--R22,
--(C.sub.0-C.sub.4)-alkyl-C(O)--O--C(R11, R19)-O--C(O)--O--R12,
--NH--C(O)--O--R10 or --O--CF.sub.3, [0123] R10 and R20 are the
same or different and are each independently a hydrogen atom or
--(C.sub.1-C.sub.6)-alkyl, [0124] R11 and R19 are the same or
different and are each independently a hydrogen atom or
--(C.sub.1-C.sub.6)-alkyl, [0125] R12 is --(C.sub.1-C.sub.6)-alkyl,
--(C.sub.1-C.sub.6)-alkyl-OH,
--(C.sub.1-C.sub.6)-alkyl-O--(C.sub.1-C.sub.6)-alkyl,
--(C.sub.3-C.sub.8)-cycloalkyl,
--(C.sub.1-C.sub.6)-alkyl-O--(C.sub.1-C.sub.8)-alkyl-(C.sub.3-C.sub.8)-cy-
cloalkyl, --(C.sub.1-C.sub.6)-alkyl-(C.sub.3-C.sub.8)-cycloalkyl,
where the cycloalkyl radical is unsubstituted or mono-, di- or
trisubstituted independently by --OH, --O--(C.sub.1-C.sub.4)-alkyl
or R10, [0126] R21 and R22 are the same or different and are each
independently a hydrogen atom, --(C.sub.1-C.sub.6)-alkyl,
--(C.sub.0-C.sub.6)-alkylene-(C.sub.3-C.sub.8)-cycloalkyl,
--O--R12, --SO.sub.t--R10 where t is the integer 1 or 2, or
--(C.sub.1-C.sub.3)-fluoroalkyl, [0127] R23 is a hydrogen atom,
--OH or --O--(C.sub.1-C.sub.4)-alkyl, [0128] X is a covalent bond
or --N(R7)- where [0129] R7 is a hydrogen atom or
--(C.sub.1-C.sub.4)-alkyl, [0130] Y is --C(O)-- or --S(O.sub.2)--,
[0131] p is the integer 1 or 2, [0132] R26 is a hydrogen atom,
[0133] R27 is a hydrogen atom, [0134] --(C.sub.1-C.sub.6)-alkyl,
--(C.sub.0-C.sub.4)-alkylene-(C.sub.3-C.sub.6)-cycloalkyl,
--(C.sub.0-C.sub.2)-alkylene-phenyl where phenyl is unsubstituted
or substituted by halogen, --(C.sub.1-C.sub.6)-alkyl,
--O--(C.sub.1-C.sub.3)-fluoroalkyl or --O--(C.sub.1-C.sub.6)-alkyl,
or --(C.sub.0-C.sub.2)-alkylene-pyridyl, R24 and R25 are the same
or different and are each independently a hydrogen atom,
--(C.sub.1-C.sub.4)-alkyl or
--(C.sub.0-C.sub.4)-alkylene-(C.sub.3-C.sub.6)-cycloalkyl, [0135]
R24 and R25, together with the carbon atom to which they are
bonded, form a cycloalkyl ring which is selected from the group of
cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and is
unsubstituted or mono-, di- or trisubstituted independently by R10
or fluorine, [0136] R24 and R25, together with the carbon atom to
which they are bonded, form a three- to six-membered
heterocycloalkyl radical selected from the group of aziridine,
azetidine, diazetidine, diaziridine, hexohydropyridazine,
hexohydropyrimidine, imidazolidine, morpholine, oxadiazinane,
oxadiazolidine, oxathianane, oxathiolane, oxazetidine, oxazolidine,
oxetane, oxirane, piperazine, piperidine, pyrazolidine,
pyrrolidine, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene,
tetrahydrothiopyran, tetrazinane, thiadiazolidine, thiazetidine,
thiaziridine, thiazolidine, thietane, thiirane, thiomorpholine,
triazetidine, triazinane or triazolidine, which is unsubstituted or
mono-, di- or trisubstituted independently by R10 or fluorine.
[0137] 7) The invention further provides the compound of the
formula Ia where the sub-ring
##STR00019##
is selected from the group of azetidine, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, 1,3-dihydroisobenzofuran, 1,3-dioxane,
1,3-dioxolane, imidazolidine, indane, morpholine, 1,3-oxazinane,
piperazine, piperidine, pyrrolidine, tetrahydrofuran, and
1,2,3,4-tetrahydronaphthalene, [0138] the sub-ring
##STR00020##
[0138] is selected from the group of azetidine, cyclopropyl,
cyclopentyl, cyclohexyl, morpholine, oxazolidine, piperidine and
pyrrolidine, and in which the two sub-rings are unsubstituted or
independently, according to the ring size, mono-, di- or
tri-substituted by R4 where [0139] R4 is
-O--(C.sub.1-C.sub.4)-alkyl, .dbd.O,
--(C.sub.0-C.sub.4)-alkylene-(C.sub.3-C.sub.6)-cycloalkyl,
--(C.sub.1-C.sub.4)-alkyl or --(C.sub.0-C.sub.4)-alkylene-phenyl
where phenyl is unsubstituted or substituted by F, Cl, Br or
--O--(C.sub.1-C.sub.4)-alkyl, [0140] X is a covalent bond or
--NH--, [0141] Y is --C(O)-- or --S(O.sub.2)--, [0142] p is the
integer 1, [0143] R27 is a hydrogen atom,
--(C.sub.1-C.sub.6)-alkyl, 4-F-benzyl or benzyl, [0144] R26 is a
hydrogen atom, [0145] R24 and R25 are the same or different and are
each independently a hydrogen atom, methyl or ethyl, [0146] R24 and
R25, together with the carbon atom to which they are bonded, form a
cyclopropyl or cyclobutyl radical, or [0147] R24 and R25, together
with the carbon atom to which they are bonded, form a piperidine
ring which is unsubstituted or substituted by
--(C.sub.1-C.sub.4)-alkyl.
[0148] 8) The invention further provides compounds of the formula I
or Ia from the group of [0149]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-3-azaspiro[5.5-
]undecane-3-carboxamide, [0150]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-8-azaspiro[4.5-
]decane-8-carboxamide, [0151]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-1,4-dioxa-8-az-
aspiro[4.5]decane-8-carboxamide, [0152]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-2-azaspiro[5.5-
]undecane-2-carboxamide, [0153]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorohexyl]-8-azaspiro[4.5-
]decane-8-carboxamide, [0154]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorohexyl]-3-azaspiro[5.5-
]undecane-3-carboxamide, [0155]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-2-(4-methoxyph-
enyl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxamide, [0156]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-4-oxo-1-phenyl-
-1,3,8-tri-azaspiro[4.5]decane-8-carboxamide, [0157]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-1,5-dioxa-9-az-
a-spiro[5.5]undecane-9-carboxamide, [0158]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-1-oxo-2,8-diaz-
aspiro[4.5]decane-8-carboxamide, [0159]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-2-methyl-1-oxo-
-2,8-diazaspiro[4.5]decane-8-carboxamide, [0160]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-3,3-dimethyl-1-
-oxa-5,9-diazaspiro[5.5]undecane-9-carboxamide, [0161]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-phenylbutyl]-8-aza-
spiro[4.5]decane-8-carboxamide, [0162]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-2,4-dioxo-1,3,-
8-triazaspiro[4.5]decane-8-carboxamide, [0163]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-2-azaspiro[4.4-
]nonane-2-carboxamide, [0164]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-2-benzyl-1-oxo-
-2,8-diazaspiro[4.5]decane-8-carboxamide, [0165]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-2-(4-fluoro
phenyl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxamide, [0166]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3-methylbutyl]-1,4-dioxaspiro[4.5-
]decane-8-carboxamide, [0167]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-3-phenyl-1,5-d-
ioxa-9-azaspiro[5.5]undecane-9-carboxamide, [0168]
N-[1-(1-cyanocyclopropylcarbamoyl)cyclohexyl]-8-azaspiro[4.5]decane-8-car-
boxamide, [0169]
N--[(S)-(1-cyanocyclopropylcarbamoyl)cyclohexylmethyl]-8-azaspiro[4.5]dec-
ane-8-carboxamide, [0170]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-9-butyl-3,9-di-
azaspiro[5.5]undecane-3-carboxamide, [0171]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-9-cyclopropyl--
3,9-diazaspiro[5.5]undecane-3-carboxamide, [0172]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3-methylbutyl]spiro[2.3]hexane-1--
carboxamide, [0173]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-phenylbutyl]-8-aza-
spiro[4.5]decane-8-carboxamide, [0174]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]spiro[2.3]hexan-
e-1-carboxamide, [0175]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-2,2-dimethyl-1-
-oxa-8-azaspiro[4.5]decane-8-carboxamide,
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-2-azaspiro[4.5-
]decane-2-carboxamide,
[0175] ##STR00021## [0176]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-1-oxa-4-azaspi-
ro[4.5]decane-4-carboxamide, [0177]
N-(1-cyanocyclopropyl)-(S)-2-[3-(1,4-dioxaspiro[4.5]dec-8-yl)ureido]-4,4--
difluoropentoxide,
[0177] ##STR00022## [0178]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)3,3-difluorobutyl]-7-cyclopropyl-2-
,7-diazaspiro[3.5]nonane-2-carboxamide, [0179]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-2-cyclopropyl--
2,7-diazaspiro[3.5]nonane-7-carboxamide, [0180]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-2-propyl-2,7-d-
iazaspiro[3.5]nonane-7-carboxamide, [0181]
N-(1-cyanocyclopropyl)-(S)-2-(8-azaspiro[4.5]decane-8-sulfonylamino)-4,4--
difluoropentoxide, [0182]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-4-cyclopropyl--
1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxamide, [0183]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-9-cyclopropyl--
1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxamide, [0184]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-2-cyclopropylm-
ethyl-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxamide,
[0184] ##STR00023## [0185]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorohexyl]-2-(4-methoxyph-
enyl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxamide, [0186]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorohexyl]-2-(4-methoxyph-
enyl)-2,8-diazaspiro[4.5]decane-8-carboxamide, [0187]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorohexyl]-2-cyclopropyl--
2,7-diazaspiro[3.5]nonane-7-carboxamide, [0188]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorohexyl]-2-cyclopropyl--
2,8-diazaspiro[4.5]decane-8-carboxamide, [0189]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorohexyl]-9-cyclopropyl--
3,9-diazaspiro[5.5]undecane-3-carboxamide, [0190]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorohexyl]-7-cyclopropyl--
2,7-diazaspiro[3.5]nonane-2-carboxamide, [0191]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorohexyl]-7-propyl-2,7-d-
iazaspiro[3.5]nonane-2-carboxamide, [0192]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-phenylbutyl]-9-cyc-
lopropyl-3,9-diazaspiro[5.5]undecane-3-carboxamide, [0193]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-phenylbutyl]-2-cyc-
lopropyl-2,7-diazaspiro[3.5]nonane-7-carboxamide, [0194]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-phenylbutyl]-2-pro-
pyl-2,7-diazaspiro[3.5]nonane-7-carboxamide, [0195]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-phenylbutyl]-7-cyc-
lopropyl-2,7-diazaspiro[3.5]nonane-2-carboxamide, [0196]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-6-azaspiro[2.5-
]octane-6-carboxamide, [0197]
N--[(S)-1-(cyanomethylcarbamoyl)-3,3-difluorobutyl]-6-azaspiro[2.5]octane-
-6-carboxamide, [0198]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorohexyl]-6-azaspiro[2.5-
]octane-6-carboxamide, [0199]
N--[(S)-1-(4-cyano-1-methylpiperidin-4-ylcarbamoyl)-3,3-difluorobutyl]-6--
azaspiro[2.5]octane-6-carboxamide, [0200]
N--[(S)-1-(4-cyano-1-methylpiperidin-4-ylcarbamoyl)-3,3-difluorohexyl]-6--
azaspiro[2.5]octane-6-carboxamide, [0201]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoropentyl]- or
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-phenylbutyl]-6-aza-
spiro[2.5]octane-6-carboxamide.
[0202] The terms "(C.sub.1-C.sub.3)-alkyl",
"(C.sub.1-C.sub.4)-alkyl" or "(C.sub.1-C.sub.10)-alkyl" are
understood to mean hydrocarbyl radicals whose carbon chain is
straight or branched and contains from 1 to 3, from 1 to 4 or from
1 to 10 carbon atoms, for example methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl,
2,3-dimethylbutyl, neohexyl, heptyl, octanyl, nonanyl or
decanyl.
[0203] The terms "--(C.sub.0-C.sub.3)-alkylene",
"--(C.sub.0-C.sub.4)-alkylene" or "--(C.sub.0-C.sub.5)-alkylene"
are understood to mean hydrocarbyl radicals whose carbon chain is
straight or branched and contains from 1 to 3, from 1 to 4 or from
1 to 5 carbon atoms, for example methylene, ethylene, propylene,
isopropylene, isobutylene, butylene, tert-butylene, isopentylene or
neopentylene. "--C.sub.0-Alkylene" is a covalent bond.
[0204] The term "(C.sub.1-C.sub.8)-alkoxy" is understood to mean
radicals such as --O--(C.sub.1-C.sub.8)-alkyl where
--(C.sub.1-C.sub.8)-alkyl is bonded by a carbon atom to an oxygen
atom.
[0205] The radical "--C(O)-" is understood to mean a keto or
aldehyde radical.
[0206] The "carbamimidoyl" radical is understood to mean a
--C(NH.sub.2).dbd.NH radical.
[0207] The term "--(C.sub.3-C.sub.8)-cycloalkyl" is understood to
mean radicals which derive from 3- to 8-membered monocycles such as
the monocycles cyclopropane, cyclobutane, cyclopentane,
cyclohexane, cycloheptane or cyclooctane.
[0208] The term "aryl" is understood to mean aromatic carbon
radicals having from 6 to 14 carbon atoms in the ring. Aryl
radicals are, for example, phenyl, indanyl, indenyl, naphthyl,
1,2,3,4-tetrahydronaphthyl, biphenylyl, 2-biphenylyl, 3-biphenylyl,
4-biphenylyl, anthryl or fluorenyl.
[0209] The term "a saturated or partly unsaturated
--(C.sub.3-C.sub.11)-cycloalkyl in which cycloalkyl is unbridged,
bridged or fused" is understood to mean radicals, for example
compounds which derive from 3- to 11-membered mono-, bicycles,
bridged cycles or spirocycles: for example from the monocycles such
as cyclopropane, cyclobutane, cyclopentane, cyclohexane,
cycloheptane or cyclooctane, for example from the bicycles such as
bicycloheptane, bicyclo[4.2.0]octane, octahydroindene, decalin,
decahydro-benzocycloheptene or dodecahydroheptalene, for example
from the bridged cycles such as bicyclo[3.1.1]heptane,
bicyclo[2.2.1]heptane, bicyclo[3.3.0]octane or
bicyclo[2.2.2]octane, or, for example, from the spirocycles such as
spiro[2.5]octane and spiro[3.4]octane.
[0210] The term "a saturated or partly unsaturated three- to
eleven-membered heterocycle which, according to the ring size, may
contain one, two, three or four identical or different heteroatoms
from the group of oxygen, nitrogen and sulfur, and in which the
heterocycle is unbridged, bridged or fused" is understood to mean
ring systems which have from three to eleven ring atoms and
contain, as well as the carbon atoms, according to the ring size,
one, two, three or four identical or different heteroatoms from the
group of oxygen, nitrogen and sulfur. Examples of these ring
systems are ring systems such as azepane, azepine, azetidine,
aziridine, azirine, azocane, benzimidazoline,
2,3-dihydrobenzo[b]thiophene, 1,3-dihydrobenzo[c]thiophene,
2,3-dihydrobenzofuran, 2,3-dihydrobenzooxazole,
2,3-dihydrobenzothiazole, 1,3-dihydroisobenzofuran,
2,3-dihydroisoxazole, 2,5-dihydroisoxazole, 4,5-dihydro-isoxazole,
benzo[1,3]dioxole, 1,4-diazepane, 1,2-diazepine, 1,3-diazepine,
1,4-diazepine, diaziridine, diazirine, 1,4-diazocane, dioxane,
1,3-dioxane, dioxazin, 1,4-diozocane, dioxole, dioxolane,
1,3-dioxolane, 1,3-dioxolene, imidazoline, imidazolidine, indane,
indoline, isoindoline, isothiazolidine, isothiazoline, isoxazoline,
isoxazolidine, 2-isoxazoline, morpholine, 1,2-oxathiepane,
1,2-oxathiolane, 1,4-oxazepane, 1,2-oxazine, 1,3-oxazine,
1,4-oxazine, oxazinane, 1,3-oxazinane, oxazocane, oxaziridine,
oxazolidine, oxetane, oxirane, oxocane, piperazine, piperidine,
pyran, pyrazoline, pyrazolidine, pyrrolidine, pyrrolidinone,
pyrroline, tetrahydroquinoline, tetrahydrofuran,
tetrahydroisoquinoline, 1,2,3,4-tetrahydronaphthalene,
tetrahydropyran, tetrahydropyridine, tetrazine, thiadiazine,
1,2-thiazine, 1,3-thiazine, 1,4-thiazine, thiazolidine, thiazoline,
thietane, thiomorpholine, thiopyran, 1,2,3-triazine, 1,2,4-triazine
or 1,3,5-triazine.
[0211] Spiro compounds are compounds of two or three rings in
which, in each case, one ring atom belongs to two rings in common.
Preference is given to spiro compounds which consist of two rings
in which, in each case, one ring atom belongs to two ring atoms in
common. This ring atom is either a carbon atom or a nitrogen atom,
preferably a carbon atom. The spiro linkage of the two sub-rings
may be via all conceivable positions. Preferred spiro compounds in
all possible stereoisomeric forms are:
##STR00024## ##STR00025##
[0212] The term "halogen" is understood to mean fluorine, chlorine,
bromine or iodine, preferably fluorine, chlorine or bromine,
especially fluorine.
[0213] The term "Het ring" or "Het" is understood to mean ring
systems which have 3 from 15 carbon atoms, are present in one, two
or three ring systems bonded to one another and which, according to
the ring size, contain one, two, three or four identical or
different heteroatoms from the group of oxygen, nitrogen or sulfur.
Examples of these ring systems are the acridinyl, azepanyl,
azepinyl, azetidinyl, aziridinyl, benzimidazolinyl, benzimidazolyl,
benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,
benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,
benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl,
quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,
quinuclidinyl, chromanyl, chromenyl, cinnolinyl,
decahydroquinolinyl, dibenzofuranyl, dibenzothiophenyl,
dihydrofuran[2,3-b]-tetrahydrofuranyl, dihydrofuranyl, dioxolyl,
dioxanyl, 2H, 6H-1,5,2-dithiazinyl, furanyl, furazanyl,
homomorpholinyl, imidazolidinyl, imidazolinyl, imidazolyl,
1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,
isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,
isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolidinyl,
2-isothiazolinyl, isothiazolyl, isoxazolyl, isoxazolidinyl,
2-isoxazolinyl, morpholinyl, naphthyridinyl,
octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,
oxazolidinyl, oxazolyl, oxazolidinyl, oxothiolanyl, pyrimidinyl,
phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,
phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,
piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl,
pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl,
pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl,
pyridothiophenyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl,
pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyridinyl,
6H-1,2,5-thiadazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,
thienyl, thienoimidazolyl, thienooxazolyl, thienopyridine,
thienothiazolyl, thiomorpholinyl, thiophenyl, triazinyl,
1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl
and xanthenyl radicals.
[0214] The term "--(C.sub.1-C.sub.3)-fluoroalkyl" is understood to
mean a partially or completely fluorinated alkyl radical which
derives, for example, from the following radicals: --CF.sub.3,
--CHF.sub.2, --CH.sub.2F, --CHF--CF.sub.3, --CHF--CHF.sub.2,
--CHF--CH.sub.2F, --CH.sub.2--CF.sub.3, --CH.sub.2--CHF.sub.2,
--CH.sub.2--CH.sub.2F, --CF.sub.2--CF.sub.3, --CF.sub.2--CHF.sub.2,
--CF.sub.2--CH.sub.2F, --CH.sub.2--CHF--CF.sub.3,
--CH.sub.2--CHF--CHF.sub.2, --CH.sub.2--CHF--CH.sub.2F,
--CH.sub.2--CH.sub.2--CF.sub.3, --CH.sub.2--CH.sub.2--CHF.sub.2,
--CH.sub.2--CH.sub.2--CH.sub.2F, --CH.sub.2--CF.sub.2--CF.sub.3,
--CH.sub.2--CF.sub.2--CHF.sub.2, --CH.sub.2--CF.sub.2--CH.sub.2F,
--CHF--CHF--CF.sub.3, --CHF--CHF--CHF.sub.2, --CHF--CHF--CH.sub.2F,
--CHF--CH.sub.2--CF.sub.3, --CHF--CH.sub.2--CHF.sub.2,
--CHF--CH.sub.2--CH.sub.2F, --CHF--CF.sub.2--CF.sub.3,
--CHF--CF.sub.2--CHF.sub.2, --CHF--CF.sub.2--CH.sub.2F,
--CF.sub.2--CHF--CF.sub.3, --CF.sub.2--CHF--CHF.sub.2,
--CF.sub.2--CHF--CH.sub.2F, --CF.sub.2--CH.sub.2--CF.sub.3,
--CF.sub.2--CH.sub.2--CHF.sub.2, --CF.sub.2--CH.sub.2--CH.sub.2F,
--CF.sub.2--CF.sub.2--CF.sub.3, --CF.sub.2--CF.sub.2--CHF.sub.2 or
--CF.sub.2--CF.sub.2--CH.sub.2F.
[0215] The terms "R2 and R3", "R19 and R11", "R13 and R14" or "R24
and R25, together with the carbon atom to which they are bonded,
form a three- to six-membered cycloalkyl ring" are understood to
mean cycloalkyl radicals such as cyclopropyl, cyclobutyl,
cyclopentyl or cyclohexyl.
[0216] The terms "R2 and R3" or "R24 and R25, together with the
carbon atom to which they are bonded, form a three- to six-membered
heterocycle alkyl radical" are understood to mean radicals such as
aziridine, azetidine, diazetidine, diaziridine,
hexohydropyridazine, hexohydropyrimidine, imidazolidine,
morpholine, oxadiazinane, oxadiazolidine, oxathianane, oxathiolane,
oxazetidine, oxazolidine, oxetane, oxirane, piperazine, piperidine,
pyrazolidine, pyrrolidine, tetrahydrofuran, tetrahydropyran,
tetrahydrothiophene, tetrahydrothiopyran, tetrazinane,
thiadiazolidine, thiazetidine, thiaziridine, thiazolidine,
thietane, thiirane, thiomorpholine, triazetidine, triazinane or
triazolidine.
[0217] The term "R21 and R22 together with the nitrogen atom to
which they are bonded form a four- to eight-membered monocyclic
heterocyclic ring which, as well as the nitrogen atom, may
additionally, according to the ring size, also contain one or two
identical or different heteroatoms from the group of oxygen,
nitrogen and sulfur" is understood to mean radicals such as
azepane, azepine, azetidine, dioxazole, dioxazine, 1,4-diazepane,
1,2-diazepine, 1,3-diazepine, 1,4-diazepine, imidazole,
imidazoline, imidazolidine, isothiazole, isothiazolidine,
isothiazoline, isoxazole, isoxazoline, isoxazolidine,
2-isoxazoline, morpholine, [1,4]oxazepane, oxazole, piperazine,
piperidine, pyrazine, pyrazole, pyrazoline, pyrazolidine,
pyridazine, pyridine, pyrimidine pyrrole, pyrrolidine,
pyrrolidinone, pyrroline, tetrahydropyridine, tetrazine, tetrazole,
thiazole, thiadiazole, thiazolidine, thiazoline, thiomorpholine,
1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or
1,2,4-triazole.
[0218] The term "two adjacent R4, together with the ring atoms to
which they are bonded, form a four- to eight-membered heterocycle
or phenyl which, together with the sub-ring to which the
heterocycle or the phenyl is fused, forms a bicyclic system" is
understood to mean compounds which consist of two connected ring
systems in which one ring constitutes the sub-ring
##STR00026##
and the other ring forms a partly saturated or aromatic ring system
which, according to the ring size, contains one, two or three
identical or different heteroatoms from the group of oxygen,
nitrogen and sulfur. Examples of these ring systems are radicals
such as benzoimidazole, benzoisothiazole, benzoisoxazole,
benzo[1,3]dioxole, benzofuranyl, benzothiazole, benzoisoxazole,
benzothiofuran, benzothiophene, benzo[1,3]oxathiole, benzoxazole,
benzothiazole, benzotriazolyl, quinazoline, quinazolone, quinoline,
4H-quinolizine, quinoxaline, chromane, chromene, cinnoline,
2,3-dihydrobenzo[1,4]dioxine, 2,3-dihydrobenzofuranyl,
1,3-dihydroisobenzofuran, 3,4-dihydro-2H-benzo[1,4]oxazine,
2,3-dihydrobenzooxazole, 2,3-dihydrobenzothiazole,
1,3-dihydrobenzo[c]thiophene, 2,3-dihydrobenzo[b]thiophene,
indazole, indole, indoline, isobenzofuran, isoquinoline,
isochromane, isoindazole, isoindole, isoindoline,
7-oxa-bicyclo[4.2.0]octa-1,3,5-triene, phthalazine,
2,3,4,5-tetrahydro-1H-benzo[b]azepine,
6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene,
3,4,5,6-tetrahydro-2H-benzo[b][1,4]oxazozine, tetrahydroquinoline,
1,2,3,4-tetrahydroquinoxaline or tetrahydroisoquinoline.
[0219] The term ".dbd.O" is understood to mean an oxo radical as in
carbonyl (--C(O)--) or sulfonyl or sulfoxide (S(O).sub.2 or
S(O)).
[0220] The sub-structure
##STR00027##
in the compound of the formula Ia is understood to mean a methylene
radical in the case that p is 1 and an ethylene radical in the case
that p is 2.
[0221] The inventive compounds can be prepared by well-known
processes or by processes described here.
[0222] The invention further relates to a process for preparing the
compounds of the formulae I and Ia and/or a stereoisomeric form of
the compound of the formulae I and Ia and/or a physiologically
compatible salt of the compound of the formulae I and Ia and/or a
solvate or hydrate of the compound of the formulae I and Ia and/or
an N-oxide of the compounds of the formula I, which comprises
a) reacting a compound of the formula II
##STR00028## [0223] where A and B are each as defined in the
compound of the formula I with a compound of the formula IIIa or
IIIb or IIIc
[0223] ##STR00029## [0224] where X, R1, R2 and R3 are each as
defined in the compound of the formula I, PG is an ester protecting
group and "activated" means that the amine is present in an
activated form, for example as a chlorocarbonyl compound, to give a
compound of the formula IVa or IVb
[0224] ##STR00030## [0225] and reacting the resulting compounds of
the formula IVa or IVb, after converting the ester to the
carboxylic acid, with Z to give the compound of the formula I, or
[0226] b) reacting a compound of the formula Va or Vb where A, B, X
and Y are each as defined in the compound of the formula I
[0226] ##STR00031## [0227] with a compound of the formula VI where
R1, R2 and R3 are each as defined in the compound of the formula I
and PG is an ester protecting group
[0227] ##STR00032## [0228] to give a compound of the formula IVa or
IVb, and reacting the resulting compound of the formula IVa or IVb,
after converting the ester protecting group to the carboxylic acid,
with Z to give the compound of the formula I, or [0229] c) reacting
a compound of the formula VIIIa or VIIb where A, B and X are each
as defined in the compound of the formula I
[0229] ##STR00033## [0230] with a compound of the formula VI
[0230] ##STR00034## [0231] to give a compound of the formula VIIIa
or VIIIb and reacting the resulting compound of the formula VIIIa
or VIIIb, after converting the ester to the corresponding
carboxylic acid, with Z to give the compound of the formulae I and
Ia, or [0232] d) reacting a compound of the formula IX
[0232] ##STR00035## [0233] with an amine Z where Z is as defined in
the compound of the formula Ito give a compound of the formula
X
[0233] ##STR00036## [0234] and then converting the compound X thus
obtained in a protecting group elimination to give a compound of
the formula XI
[0234] ##STR00037## [0235] and then reacting this compound XI with
a compound Va or Vb, as detailed under b), to give the inventive
compound of the formulae I and Ia, or [0236] e) separating a
compound of the formulae I and Ia prepared by processes a), b), c)
or d), or a suitable precursor of the formulae I and Ia which,
owing to its chemical structure, occurs in enantiomeric or
diastereomeric forms, into the pure enantiomers or diastereomers by
salt formation with enantiomerically pure salts or bases,
chromatography on chiral stationary phases or derivatization by
means of chiral enantiomerically pure compounds such as amino
acids, separating the diastereomers thus obtained, and eliminating
the chiral auxiliary groups, or [0237] f) either isolating the
compound of the formulae I and Ia prepared by processes a), b), c)
or d) in free form or releasing it from physiologically
incompatible salts or, in the case of the presence or acidic or
basic groups, converting it to physiologically acceptable salts, or
[0238] g) converting the compound of the formulae I and Ia prepared
by processes a), b), c) or d), or a suitable precursor of the
formulae I and Ia which, owing to its chemical structure, is
capable of forming an N-oxide to an N-oxide or, in the case of the
presence of an N-oxide, converting it to the free amine or the salt
of an amine.
[0239] The synthesis of the inventive products can also proceed on
the basis of three starting materials, any variation of the
components which lead to the inventive structures being possible.
For the sake of simplicity, the possible syntheses are described
through these three components; however, this is not intended to
constitute any restriction on the further means of synthesis.
[0240] For example, component A may be a spiro-amine:
[0240] ##STR00038## [0241] For example, component B may be an amino
acid derivative:
[0241] ##STR00039## [0242] for example, component C may be an amino
nitrile:
##STR00040##
[0243] It is a preferred route to prepare, from these three
starting materials by selection of suitable derivatives of these
components, for example protected or modified precursors or
precursors with defined stereochemistry, the inventive compounds
through suitable coupling reactions, possibly after activation with
reactive reagents such as known peptide coupling reagents or
reagents which lead to activated urea precursors. Methods of
peptide coupling are described, for instance, in Bodanszky (M.
Bodanszky, Principles of Peptide Synthesis, 2nd ed, Springer,
Berlin, 1993). Protecting groups, their introduction, detachment
and stability are described, for example, in Greene (T. W. Greene,
P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd ed,
Wiley, New York, 1999). The preparation of ureas is described in
detail, for example, in G. Sartori; R. Maggi, Acyclic and cyclic
ureas. Science of Synthesis (2005), 18, 665-758.
[0244] It is possible for many different suitable activation and
coupling reagents which are known to those skilled in the art and
some of which differ in their chemistry to be used. Merely by way
of example, mention is made of carbodiimides, uronium salts or else
chloroformic esters for carboxylic acid activation, and of
phosgene, carbonyldiimidazole or else chloroformic esters for the
preparation of activated urea precursors, and of chlorosulfonic
acid or sulfur trioxide for the preparation of activated
sulfonylurea precursors.
[0245] It is equally possible for the sequence of coupling to be
varied, or else the individual component or the two-component unit
(which has been obtained by coupling two adjacent individual
components) on which the activation is undertaken, or for different
protecting groups to be used, followed by the addition of the
component which is still absent or of the components which are
still absent. It is also possible to change the protecting groups,
for example protecting group detachments on completion of coupling
or at the end of the synthesis, to prepare the compound of the
formulae I and Ia.
[0246] Moreover, the compound of the formulae I and Ia can be
prepared via route 1a:
Route 1a
##STR00041##
[0248] The component B--amino acid derivative --used is a suitable
ester, for example a methyl ester, but many other ester protecting
groups are also possible.
[0249] This derivative is activated on the nitrogen to give a urea
precursor, for example by reaction with triphosgene, diphosgene or
phosgene itself to give an isocyanate, so that a urea is formed by
subsequent reaction with the spiro-amine A. However, many other
types of activation are also possible; for example, reaction with
carbonyldiimidazole affords the activated imidazolide, reaction
with 4-nitrophenyl chloroformate affords the corresponding
carbamate, and reaction with various similar activating carbonate
reagents such as bis-succinimidyl carbonate or bis(4-nitrophenyl)
carbonate affords corresponding derivatives. The analogous
sulfur-containing derivatives (thiourea analogs) can be obtained
correspondingly by the use of thiophosgene. However, it has to be
taken into account that the strength of activation by the reagents
listed is different, i.e. the subsequent reaction with the
secondary spiro-amine can proceed at different speed or else afford
very different yields or by-products.
[0250] Moreover, it might be necessary to achieve a preactivation
by silylating the amine with, for example, trimethylsilyl chloride
or bistrimethylsiliylacetamide or
bistrifluoromethyltrimethylsilylacetamide in order that the
actually activated urea precursor can form more easily. In
addition, it might be advantageous in some cases to proceed from a
free amino acid and to silylate it both on the nitrogen and on the
carboxylic acid with one of the silylating reagents mentioned or
else other suitable silylating reagents, and then to form the
isocyanate.
##STR00042##
[0251] Next, the ester is cleaved under conditions which cause a
minimum level of side reactions on the molecule, in the case of the
methyl ester preferably under basic conditions, for example with
NaOH or LiOH as a base, and it is advisable to avoid base excesses
or long reaction times. In the case of a silyl protecting group, it
may, though, also be sufficient to achieve ester cleavage by
aqueous treatment, possibly with addition of a little mineral
acid.
[0252] Before the amide bond can be formed with the 3rd component,
the aminonitrile, the carboxylic acid is generally released from
the salt with a mineral acid after the basic cleavage.
[0253] Subsequently, the peptide coupling can be effected by a
multitude of methods known to those skilled in the art, as already
mentioned above, if appropriate with addition of further auxiliary
reagents for increasing the coupling efficiency or suppressing
racemization.
Route 1b:
##STR00043##
[0255] The same components as described under route 1a are used. In
contrast to route 1a, however, the activation to give the urea
precursor is not effected on component B, the amino acid
derivative, but rather on component A, the spiro-amine. Since it
is, however, a secondary amine, reactivities and yields are often
changed compared to route 1a. For example, it is, though, possible
to activate the spiro-amine as the chlorocarbonyl derivative by
reaction with phosgene, triphosgene or diphosgene, and then to
react the latter with the abovementioned amino acid ester. The
abovementioned amino acid can also be used in the activated
silylated form.
[0256] The further reaction, i.e. release of the carboxylic acid
and coupling with the amine component C, is then effected as
described under 1a.
Route 2a
##STR00044##
[0258] The starting material is a suitable N-terminally protected
amino acid derivative B. This is first coupled with the
aminonitrile C; in this reaction, the known methods of peptide bond
formation can again be used. Subsequently, the N-terminal
protecting group is eliminated and the elimination product is
converted to the activated urea precursor as described under 1a.
Under some circumstances, it is of particular significance here to
use the protecting groups whose detachment conditions are
compatible with the functionalities on the overall molecule B--C.
This activated derivative, for example the isocyanate, is
subsequently reacted with the spiro-amine to give the inventive
compound I.
Route 2b
##STR00045##
[0260] Alternatively, it is also possible here, analogously to the
route described under 1b first to activate the spiro-amine A in
order then to perform the reaction with component B--C to give the
urea.
[0261] Chlorosulfonylamines or inventive sulfonylureas are prepared
according to the following scheme:
##STR00046##
[0262] The synthesis of sulfonylureas is widely described. A
frequently used method proceeds from an activation of the amines to
give sulfonyl chlorides by reaction with preferably chlorosulfonic
acid, and subsequent chlorination of the resulting sulfonic acid
with, for example, phosphorus pentachloride or phosphorus
oxychloride, followed by the reaction with the second amino
component and a suitable base. Equally, it is also possible to use
SO.sub.3 in the first stage of the synthesis.
[0263] Moreover, it is also possible to achieve the desired
conversion with sulfonyl chloride. Preference is given to
undertaking the reaction on the secondary spiro-amine unit,
followed by the reaction, for example, of the amino acid-amine,
protected as the ester. Subsequently, the ester is cleaved and
reacted with the aminonitrile unit.
[0264] Alternatively, it is also possible to react the activated
spiro unit with the amino acid-amidonitrile, prepared from the
N-terminally protected amino acid by coupling with the aminonitrile
unit followed by the protecting group detachment.
[0265] Bisamides are prepared starting from amino acid units
according to the following scheme:
##STR00047##
[0266] When the spiro unit is not present as a secondary amine but
rather as a carboxylic acid, there is attachment to the amino acid
via an amide bond. This can be effected in the synthesis either
first, in which case an amino acid ester is used, followed as
described above in the analogous case 1b by ester cleavage and
amide coupling with the aminonitrile unit, or, when an amino
acid-amidonitrile unit is used, as the second coupling stage in the
synthesis, in each case accompanied by appropriate protecting group
manipulations, as described above in case 2b.
[0267] Optically active carbon atoms in the inventive compounds of
the formulae I and Ia may each independently be present in R or S
configuration. The compounds of the formulae I and Ia may be
present in the form of the pure enantiomers or pure diastereomers
or in the form of mixtures in any proportions of the enantiomers
and/or diastereomers, for example in the form of their racemates or
enantiomeric diastereomer pairs. The present invention thus relates
to pure enantiomers and mixtures of the enantiomers, and equally to
pure diastereomers and mixtures of the diastereomers. The invention
likewise encompasses mixtures of two or of more than two
stereoisomers of the formulae I and Ia and likewise all possible
mixing ratios of these stereoisomers in the mixtures. In the case
that the compounds of the formulae I and Ia are present in the form
of E or Z isomers, or cis or transisomers, or as a "spiran", the
invention relates in each case both to the pure E and pure Z
isomers, and to the pure cis or pure transisomers, and likewise,
entirely analogously, to the corresponding spiroisomers, and also
E/Z or cis/trans mixtures in any ratio. The invention likewise
encompasses all tautomeric forms of the inventive compounds of the
formulae I and Ia.
[0268] The compound of the formulae I and Ia is, when it occurs as
a mixture of diastereomers or enantiomers or is obtained as
mixtures thereof in the synthesis selected, separated into the pure
stereoisomers, either by chromatography on a chiral or achiral
support material, or, when the racemic compound of the formulae I
and Ia is capable of salt formation, by fractional crystallization
of the diastereomeric salts formed with an optically active base or
acid as an auxiliary. Suitable chiral stationary phases for
thin-layer or column chromatography separation of enantiomers are,
for example, modified silica gel supports (so-called Pirkle phases)
and high molecular weight carbohydrates such as triacetylcellulose.
For analytical purposes, gas chromatography methods on chiral
stationary phases can also be employed after appropriate
derivatization known to those skilled in the art. For enantiomer
separation of the racemic carboxylic acids, an optically active,
generally commercially available base such as (-)-nicotine, (+)-
and (-)-phenylethylamine, quinine bases, L-lysine or L- and
D-arginine are used to form the differently soluble diastereomeric
salts, the less soluble component is isolated as a solid, the more
soluble diastereomer is separated from the mother liquor, and the
pure enantiomers are obtained from the diastereomeric salts thus
obtained. In a manner similar in principle, the racemic compounds
of the formulae I and Ia which contain a basic group, for example
an amino group, can be converted to the pure enantiomers with
optically active acids, for example (+)-camphor-10-sulfonic acid,
D- and L-tartaric acid, D- and L-lactic acid, and also (+)- and
(-)-mandelic acid. It is also possible to convert chiral compounds
which contain alcohol or amine functions to the corresponding
esters or amides with correspondingly activated or optionally
N-protected enantiomerically pure amino acids, or, conversely, to
convert chiral carboxylic acids to the amides with
carboxy-protected enantiomerically pure amino acids, or to the
corresponding chiral esters with enantiomerically pure
hydroxycarboxylic acids such as lactic acid. The chirality of the
amino acid or alcohol radical introduced in enantiomerically pure
form can then be utilized to separate the isomers by undertaking a
separation of the diastereomers now present by crystallization or
chromatography on suitable stationary phases, and then detaching
the entrained chiral molecular moiety again by means of suitable
methods.
[0269] Furthermore, the possibility arises for some of the
inventive compounds to use diastereomerically or enantiomerically
pure starting materials to prepare the skeleton structures. This
also allows different or simplified processes for purifying the end
products to be used. These starting materials have been prepared
beforehand in enantiomerically or diastereomerically pure form by
literature processes. To this end, for example, it is also possible
to use enzymatic processes. It is possible either to use those
enzymatic processes which proceed enantio- or diastereoselectively
in one synthesis step, i.e. afford one compound selectively, or
else in the sense of a kinetic enzymatic synthesis or cleavage in
such a way that, for example, an enantiomer or diastereomer already
present is converted highly preferentially in the enzymatic
reaction, for example in the sense of a selective acylation or
esterification or acyl cleavage or ester cleavage. Reactions used
successfully are, for example, acylation reactions with lipases or
acylase cleavages of N-acetyl compounds, or protease-mediated
esterifications in organic solvents or ester cleavages, but many
other possibilities are also conceivable.
[0270] When amino acid derivatives are used, they are frequently
commercially available already in enantiomerically pure form. In
the case of non-proteinogenic amino acids, they may, however, often
also be prepared from enantiomerically or diastereomerically pure
natural precursors, for example from proteinogenic amino acids or
else other natural chiral starting materials of the chiral pool, or
else these precursors are obtained in optically pure form by one of
the separation methods mentioned or by use of different types of
enzymatic processes and used correspondingly in the synthesis.
[0271] Acidic or basic products of the compound of the formulae I
and Ia may be present in the form of their salts or in free form.
Preference is given to pharmacologically acceptable salts, for
example alkali metal or alkaline earth metal salts or
hydrochlorides, hydrobromides, sulfates, hemisulfates, all possible
phosphates and salts of the amino acids, natural bases or
carboxylic acids. The present invention also includes all solvates
of the compounds of the general formulae I and Ia, such as
stoichiometric or nonstoichiometric hydrates or alcohol
adducts.
[0272] The preparation of physiologically compatible salts from
compounds of the formulae I and Ia capable of salt formation,
including their stereoisomeric forms, is effected in a manner known
per se. The acidic compounds of the formulae I and Ia form stable
alkali metal, alkaline earth metal or optionally substituted
ammonium salts with basic reagents such as hydroxides, carbonates,
hydrogencarbonates, alkoxides and ammonia, or organic basis, for
example methylamine, dimethylamine, ethylamine, trimethyl or
triethylamine, ethanolamine, diethanolamine or triethanolamine,
trometamol or else basic amino acids, for instance lysine,
ornithine or arginine. When the compounds of the formulae I and Ia
have basic groups, it is also possible to prepare stable acid
addition salts with strong acid. For this purpose, useful acids are
both inorganic and organic acids such as hydrochloric acid,
hydrobromic acid, sulfuric acid, hemisulfuric acid, phosphoric
acid, nitric acid, methanesulfonic acid, benzenesulfonic acid,
p-toluenesulfonic acid, 4-bromobenzenesulfonic acid,
cyclohexylamidosulfonic acid, trifluoromethylsulfonic acid,
2-hydroxyethanesulfonic acid, formic acid, acetic acid, oxalic
acid, tartaric acid, succinic acid, glycerolphosphoric acid, lactic
acid, malic acid, adipic acid, citric acid, fumaric acid, maleic
acid, malonic acid, benzoic acid, sorbic acid, gluconic acid,
glucuronic acid, palmitic acid, stearic acid or trifluoroacetic
acid. Hydrates of the compounds of the formulae I and Ia can be
prepared, for example, by (re)crystallization from an
organic-aqueous solvent mixture, for example by using such organic
solvents as dioxane, tetrahydrofuran, ethanol or methanol.
[0273] Conversely, it is also possible to prepare free acid or free
base forms of the compounds of the formulae I and Ia from the
corresponding salts. For example, a compound of the formulae I and
Ia can be released from its acid salt form by treatment with
suitable bases (such as ammonia solution, sodium hydroxide
solution). In some special cases, treatment with oxiranes can also
bring about a release; for example, hydrochlorides can be released
by treatment with methyloxirane, particularly in the case of amino
acid derivatives. Compounds of the formulae I and Ia which are
present in the form of their base salt form can be converted to the
free acid form by treatment with suitable acids (citric acid,
hydrochloric acid or sulfuric acid).
[0274] Nitrogen compounds of the formulae I and Ia may also be
present in the form of their N-oxides. These can be prepared by
various processes which are known to those skilled in the art. For
example, a nonoxidized form of a compound of the formulae I and Ia
can be oxidized to the corresponding N-oxides by treatment with a
suitable oxidizing agent (trifluoroperacetic acid, permaleic acid,
perbenzoic acid, peracetic acid, meta-chloroperbenzoic acid) in
suitable inert organic solvents. Alternatively, the N-oxides of the
compounds of the formulae I and Ia can also be prepared by using
starting materials or intermediates in the form of their N-oxides
or preparing them as such.
[0275] Compounds of the formulae I and Ia in their nonoxidized form
can also be prepared from the N-oxides of the compounds of the
formulae I and Ia by treatment with reducing reagents (such as
sulfur, sulfur dioxide, triphenylphosphine, various borohydrides,
phosphorus trichloride or -bromide and the like) in suitable inert
organic solvents.
[0276] Compounds of the formulae I and Ia which simultaneously bear
a basic and an acidic group, for example an amino or guanidino
group and a carboxyl group, may likewise be present in the form of
their zwitterions (betaines), which are likewise included within
the scope of the present invention.
[0277] The invention likewise encompasses all salts of the
compounds of the formulae I and Ia which, owing to their low
physiological tolerability, cannot be used directly in active
pharmaceutical ingredients, but, for example, are used as
intermediates on the route to the preparation of the inventive
compounds, or else as starting materials for the synthesis of the
physiologically tolerable salts. The invention further encompasses
derivatives and modifications of the compounds of the formulae I
and Ia, for example prodrugs, protected forms and other
physiologically tolerable derivatives, and equally active or
secondarily activable metabolites of the compounds of the formulae
I and Ia. In particular, the invention encompasses prodrugs and
protected forms of the compounds of the formulae I and Ia which can
be converted to the compounds of the formulae I and Ia under
physiological conditions. Suitable prodrugs of the compounds of the
formulae I and Ia are in particular those chemically modified
derivatives whose properties are modified in a desired manner, for
example in relation to improved solubility, bioavailability,
absorption, or prolonged exposure or duration of action. The
possible prodrugs are known to those skilled in the art and widely
described in the literature.
[0278] The invention also relates to medicaments characterized by
an active content of at least one compound of the formulae I and Ia
and/or of a physiologically compatible salt of the compound of the
formulae I and Ia and/or a stereoisomeric or non-stereoisomeric
form of the compound of the formulae I and Ia, together with a
pharmaceutically suitable and physiologically compatible carrier,
additive and/or other active ingredients and auxiliaries.
[0279] Owing to the pharmacological properties, the inventive
compounds are suitable for the prophylaxis, secondary prevention
and therapy of all of those disorders treatable by an inhibition of
the cysteine proteases, particularly of the cathepsins. They are
suitable both for acute treatment and for long-term therapy.
Cathepsin inhibitors can be used in the case of abnormally elevated
bone degradation, allergies, Alzheimer's disease, amyloidosis,
ARDS, arterial thrombosis, asthma, atheromas, atherosclerosis,
autoimmune disorders, bacterial infections, bronchiolitis, cerebral
hemorrhage, cerebrovascular ischemea, Huntington's chorea, chronic
inflammations, CIPD (chronic inflammatory demyelinizing
polyradiculoneuropathy), Creutzfeldt-Jakob disease, Crohn's
disease, diabetes (particularly the juvenile form), emphysema,
encephalomyelitis, endometriosis, inflammatory respiratory
disorders, inflammatory pancreatitis, epilepsy, disorders
characterized by enhanced angiogenesis, excessive respiratory
pathway elastolysis, tissue grafts, gingivitis, glomerulonephritis,
glucocorticoid-induced osteoporosis, Graves' disease,
Guillain-Barre syndrome, Hashimoto's thyroiditis, hepatitis, HIV
infection, Huntington's disease, hypercalcemia, IBD, immune
impairment, interstitial cystitis, bone fracture, bone loss,
cancers, lupus erythematosus, malaria, metachromic leukodystrophy,
metastasizing osteogenesis, metastatis, multiple sclerosis,
multiple myeloma, muscular dystrophy, myasthenia gravis,
neurodegenerative disorders, neuropathic pain, (particularly
chronic neuropathic pain; but also diabetic neuropathy,
post-therapeutic neuralgia, trigeminal neuralgia, painful diabetic
polyneuropathy, post-stroke pain, post-amputation pain, myelopathic
or radiculopathic pain, atypical facial pain and causalgia-like
syndromes), organ rejection in transplants, osteoarthritis,
osteogenesis imperfecta, osteoporosis, Paget's disease,
pancreatitis, Parkinson's disease, pemphigus vulgaris,
periodontitis, plaque rupture, Pneumocystis carinii, pneumonitis,
psoriasis, restenosis, rheumatoid arthritis, scleroderma, systemic
lupus erythematosus, trauma (brain, spinal cord), tumor cell
invasion, viral infections, tooth loss, and preferably, but not
exclusively, in the following types of cancer: breast cancer,
intestinal cancer, ovarian cancer, cervical cancer, skin cancer,
brain tumor, Kaposi's sarcoma, leukemia (B- and T-cell), lung
cancer, lymph node cancer, pancreatic cancer, prostrate cancer and
sarcomas.
[0280] Since many compounds of this invention are particularly
inhibitors of the cysteine cathepsins B, K and S, it is possible
with preference to treat disorders in which said cathepsins
contribute to the pathology or/and symptoms. This relates
particularly to: pain, especially neuropathic pain, osteoarthritis,
osteoporosis and various cancer types. This likewise relates to
various (auto)immune disorders, particularly of the rheumatoid
type, which have likewise already been listed above, and disorders
characterized by excessive elastolysis, particularly of the COPD
type, and related disorders listed above, and also cardiovascular
disorders characterized by vascular changes, such as
atherosclerosis.
[0281] The inventive medicaments can be administered
extravascularly, for example intramuscularly, subcutaneously,
intraocularly, intraarticularly, intrasynovially, perorally, orally
(buccally, perlingually, sublingually), rectally, vaginally,
(trans)dermally, pulmonally (inhalatively) or nasally or
intravascularly, for example intravenously, intraarterially, or
intracardially, in each case as an injection or infusion.
Preference is given to the oral administration form.
[0282] The invention also relates to a process for producing a
medicament, which comprises bringing a compound of the formulae I
and Ia into a suitable administration form with a pharmaceutically
suitable and physiologically compatible carrier and optionally
further suitable active ingredients, additives or auxiliaries.
[0283] Suitable solid or pharmaceutical formulation forms are, for
example, granules, powders, coated tablets, tablets,
(micro)capsules, suppositories, syrups, juices, suspensions,
emulsions, drops or injectable solutions, and also preparations
with protracted active ingredient release in whose production
customary auxiliaries such as carriers, disintegrants, binders,
coatings, swelling agents, glidants or lubricants, flavorings,
sweeteners and solubilizers are used. Frequently used auxiliaries
include magnesium carbonate, titanium dioxide, lactose, mannitol
and other sugars, talc, milk protein, gelatine, starch, cellulose
and derivatives thereof, animal and vegetable oils such as fish
oil, sunflower oil, groundnut oil or sesame oil, polyethylene
glycol and solvents such as sterile water and mono- or polyhydric
alcohols such as glycerol. Moreover, it is also possible,
particularly in the production of suspensions, to use compounds
with quite particular, specifically established surface properties.
These include, for example, dry and wet grinding, micronization,
spray drying, production of nanocrystals and similar processes, in
which changing the surface properties allows, for example,
improvement in solubilities or especially dissolution kinetics,
which achieves, for example, improved uptake of the particular
compound into the organism.
[0284] The pharmaceutical preparations are preferably produced and
administered in dosage units, each unit containing a particular
dose of the inventive compound of the formulae I and Ia as an
active constituent. In the case of solid dosage units such as
tablets, capsules, coated tablets or suppositories, this dose may
be up to about 5000 mg, but preferably from about 50 to 1000 mg,
and, in the case of injection solutions in ampule form, up to about
500 mg, but preferably from about 20 to 200 mg. For the treatment
of an adult patient of about 70 kg in weight, according to the
activity of the compound of the formulae I and Ia, daily doses of
from about 2 mg to 5000 mg of active ingredient, preferably from
about 10 mg to 1000 mg, are indicated. Under some circumstances,
however, higher or lower daily doses may also be appropriate. The
daily dose can be administered either by a single dose in the form
of a single dosage unit or else a plurality of smaller dosage
units, or else by multiple administration of divided doses at
particular intervals.
[0285] Inhibitors of the aforementioned type can be administered
even as a monotherapy or in combination or together with other
medicaments.
[0286] End products are generally determined by mass spectrometry
methods (FAB-, ESI-MS) and .sup.1H NMR (generally, unless stated
otherwise, 500 MHz in DMSO-D6); in each case, the main peak or the
two main peaks are specified. Temperatures are stated in degrees
Celsius. Abbreviations used are either explained or correspond to
the customary conventions.
[0287] Starting materials or synthesis intermediates are either
obtainable commercially or are prepared as cited or described.
1-Oxa-8-azaspiro[4.5]decane, 2-oxa-8-azaspiro[4.5]decane,
2-oxa-7-azaspiro[4.5]decane, 1-oxa-7-azaspiro[4.5]decane,
2-oxa-7-azaspiro[3.5]nonane and also analogous or alkyl-substituted
or -disubstituted derivatives are prepared as described in
WO01/87838. 1,4-Dioxa-8-azaspiro[4.5]decane,
1-oxa-4,8-diazaspiro[4.5]decane, 1,5-dioxa-9-azaspiro[5.5]undecane,
1-oxa-5,9-diazaspiro[5.5]undecane or similar and substituted
derivatives are prepared as in EP 0621267. The known method can
likewise also be employed successfully by heating the keto
precursor (for example the protected piperidone) with diols and a
catalytic amount of p-toluenesulfonic acid on a water separator.
3-Azaspiro[5.5]undecane is also obtainable, for example, from
3-azaspiro[5.5]undecane-2,4-dione; the same applies for similar
carbocyclic spiro compounds. The reduction can be effected with
LiAlH.sub.4. 2-Methyl-2,8-diazaspiro[4.5]decan-1-one, differently
2-substituted derivatives, analogous ureas and amines are described
in J. Med. Chem. 47 (8), 2037-61 (2004), or can be obtained from
the products described here by further reactions, for example
reduction. Likewise described in this publication are substituted
spiro-hydantoins and lactams with inverse amide formation (i.e.
2,8-diazaspiro[4.5]decan-3-one and derivatives), and also
imides.
[0288] Many different spirocyclic indanes, indenes, tetralones and
tetralins are commercially available.
[0289] The preparation of 6-azaspiro[2.5]octane and many further
spiro compounds is described in Bull. Soc Chim. France 10, 2572-81
(1964).
Abbreviations Used
[0290] bis(2-methoxyethyl)aminosulfur trifluoride BAST tert-butyl
tBu 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl Binap
bis(oxo-3-oxazolidinyl)phosphoryl chloride BOP-Cl
dibenzylideneacetone dba dichloromethane DCM
dicyclohexylcarbodiimide DCC diethylphosphoryl cyanide DEPC
diisopropylethylamine DIPEA 4-dimethylaminopyridine DMAP
N,N-dimethylformamide DMF
[0291] dimethyl sulfoxide DMSO 1,1'-bis(diphenylphosphino)ferrocene
DPPF 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
EDCI equivalents eq. saturated sat.
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate HATU 7-aza-1-hydroxybenzotriazole HOAt lithium
diisopropylamide LDA methanol MeOH methylmagnesium chloride
solution MeMgCl sol. methyl tert-butyl ether MTBE
N-bromosuccinimide NBS
N-chlorosuccinimide NCS
N-iodosuccinimide NIS
N-ethylmorpholine NEM
[0292] room temperature from 20.degree. C. to 25.degree. C. RT
broad singlet s.sub.b tetrahydrofuran THF trifluoroacetic acid TFA
O-((ethoxycarbonyl)cyanomethyleneamino)-N,N,N',N'-tetramethyluronium
tetrafluoroborate TOTU
[0293] Unless specified otherwise herein, the following definitions
will apply:
[0294] "Patient" means a warm blooded animal, such as for example
rat, mice, dogs, cats, guinea pigs, and primates such as
humans.
[0295] "Treat" or "treating" means to alleviate symptoms, eliminate
the causation of the symptoms either on a temporary or permanent
basis, or to prevent or slow the appearance of symptoms of the
named disorder or condition.
[0296] "Therapeutically effective amount" means a quantity of the
compound which is effective in treating the named disorder or
condition.
[0297] "Pharmaceutically acceptable carrier" is a non-toxic
solvent, dispersant, excipient, adjuvant or other material which is
mixed with the active ingredient in order to permit the formation
of a pharmaceutical composition, i.e., a dosage form capable of
administration to the patient. One example of such a carrier is a
pharmaceutically acceptable oil typically used for parenteral
administration.
[0298] The citation of any reference herein should not be construed
as an admission that such reference is available as "Prior Art" to
the instant application.
[0299] The present invention is not to be limited in scope by the
specific embodiments describe herein. Indeed, various modifications
of the invention in addition to those described herein will become
apparent to those skilled in the art from the foregoing description
and the accompanying figures. Such modifications are intended to
fall within the scope of the appended claims.
[0300] Various publications are cited herein, the disclosures of
which are incorporated by reference in their entireties.
EXAMPLES
[0301] The examples which follow were prepared analogously to the
general or specific methods specified above.
Example 1
Methyl (S)-2-benzyloxycarbonylamino-3-chlorocarbonylpropionate
[0302] Z-asp-OMe (175 g, 622 mmol) was dissolved in THF (1750 ml)
and admixed with 2 ml of DMF. 86.9 g (684 mmol) of oxalyl chloride
were dissolved in 200 ml of THF (slightly exothermic), cooled back
to room temperature (RT) and added dropwise to the solution of the
amino acid over 1 hour (h). After a further hour at RT, the
solution was initially sparged with nitrogen for 10 min,
concentrated on a rotary evaporator at a maximum of 30.degree. C.
and coevaporated repeatedly with toluene. The resulting dirty white
solid was dried to constant weight under in-house vacuum (about 1.5
mbar) and reacted further without further purification. Yield:
186.6 g (quantitative).
Example 2
Methyl (S)-2-benzyloxycarbonylamino-4-oxopentanoate
[0303] Copper(I) bromide (60.9 g, 425 mmol, 1.2 equivalents (eq.))
was introduced into a 3 liter 4-neck flask (with dropping funnel,
internal thermometer, argon inlet, rubber septa, in a cooling bath)
and admixed with 250 ml of THF. A separate flask was initially
charged at 10.degree. C. with lithium bromide (75 g, 864 mmol, 2.4
eq.) and admixed with 470 ml of THF under argon. On completion of
dissolution and recooling to RT, this solution was transferred to
the suspension of the copper bromide. The resulting colorless to
slightly greenish solution was cooled to -60.degree. C., and
methylmagnesium chloride (141 ml of a 3.0 M solution in THF, 423
mmol) was added within 15 min. A thick yellowish precipitate formed
and the temperature rose to RT. After cooling again to -60.degree.
C., the solution from example 1 (prepared from 106 g of methyl
(S)-2-benzyloxycarbonylamino-3-chlorocarbonylpropionate, 353 mmol,
and 360 ml of THF) was added over about 30 min and the temperature
was kept below -25.degree. C. After the addition had ended, the
mixture was stirred for another 1 h, and solid ammonium chloride
(30 g) was added at -15.degree. C. After a further 2 h, the mixture
was filtered, the filtrate was diluted with 400 ml of heptane and
200 ml of saturated ammonium chloride solution were added. Once the
mixture had been stirred at RT for 1 h, the organic phase was
removed and washed repeatedly, and the aqueous phases were
reextracted with ethyl acetate. The combined organic phases were
dried over sodium sulfate, concentrated on a rotary evaporator
under reduced pressure and chromatographed on 1 kg of silica gel
with 1:3 to 1:1 ethyl acetate/heptane. After the products had been
combined and dried under reduced pressure, 83 g (84% yield) of a
white solid were obtained. .sup.1H NMR (300 MHz, CDCl.sub.3): 7.4
(m, 5H); 5.78 (m, 1H); 5.18 (s, 2H); 4.6 (s, 1H); 3.75 ("s", 3H);
3.3-2.9 (2dd, 2H); 2.2 (s, 3H)
Example 3
Methyl (S)-2-benzyloxycarbonylamino-4-oxoheptanoate
[0304] The preparation was effected analogously to example 2, with
the difference that N-propylmagnesium chloride (2 M in diethyl
ether) was now used and a chromatographic purification was
dispensed with. Instead, the resulting dark crude product was taken
up in 1:1 DCM/heptane and filtered through Celite. After treatment
with activated carbon and filtration, the desired product was
obtained in 93% yield.
[0305] .sup.1H NMR (300 MHz, CDCl.sub.3): 7.4 (m, 5H); 5.78 (m,
1H); 5.17 (s, 2H); 4.6 (s, 1H); 3.73 ("s", 3H); 3.3-2.9 (2dd, 2H);
2.4 (m, 2H); 1.6 (m, 2H, overlapping); 0.9 (m, 3H)
Example 4
Methyl (S)-2-benzyloxycarbonylamino-4,4-difluoropentaoate
[0306] BAST (Deoxofluor, 60 g, 271 mmol, 2.95 eq.) was initially
charged in a 1 liter flask made of inert plastic and admixed with
the ketone from example 2, dissolved/suspended in 40 ml of
dichloromethane. After a reaction time of 1 day and again after 12
h, in each case 25 ml (113 mmol) of BAST were added and the mixture
was stirred further at RT. After a further 12 h, dichloromethane
was added and the resulting solution was rapidly added dropwise to
an ice-cold saturated sodium hydrogencarbonate solution while
keeping the temperature below 30.degree. C. The organic phase was
removed, the aqueous phase was extracted repeatedly with
dichloromethane and the combined organic phases were washed with
water, 1 N HCl and saturated in NaCl solution, dried over sodium
solvate and concentrated under reduced pressure. The brown oil was
then chromatographed on silica gel (3:1 heptane/MTBE to 2:1).
[0307] Product fractions were combined and concentrated by
evaporation under reduced pressure.
[0308] Yield: 22.3 g, 56%. .sup.1H NMR (300 MHz, CDCl.sub.3): 7.4
(m, 5H); 5.45 (m, 1H); 5.18 (s, 2H); 4.6 (s, 1H); 3.78 ("s", 3H);
2.4 (m, 2H); 1.7 (m, 3H)
Example 5
Methyl (S)-2-benzyloxycarbonylamino-4,4-difluoroheptanoate
[0309] The preparation was effected analogously to example 4.
[0310] .sup.1H NMR (300 MHz, CDCl.sub.3): 7.4 (m, 5H); 5.46 (m,
1H); 5.17 (s, 2H); 4.6 (m, 1H); 3.77 ("s", 3H); 2.4 (m, 2H); 1.8
(m, 2H, overlapping); 1.5 (m, 2H); 0.95 (m, 3H)
[0311] All further reactions in the series of the
4,4-difluoroheptanoic acid derivatives to give the inventive end
products were conducted entirely analogously to the corresponding
pentanoic acid derivatives.
Example 6
Methyl (S)-2-amino-4,4-difluoropentanoate hydrobromide
[0312] 10 g of the compound from example 4 were admixed at RT with
35 ml of 33% HBr in glacial acetic acid and stirred for 40 min.
Subsequently, 400 ml of cold diethyl ether were added and the
reaction mixture was stored at 4.degree. C. for 3 h. The
precipitated product was filtered off with suction through a glass
frit, washed thoroughly with cold ether and freed of solvent
residues under reduced pressure. It can be used directly in the
next reaction. Yield: 6.67 g (82%)
[0313] .sup.1H NMR: 8.5 (s.sub.b, 3H); 4.3 (t, 1H); 3.76 (s, 3H);
2.53 (m, 2H); 1.7 (t, 3H).
Example 7
Methyl (S)-4,4-difluoro-2-isocyanatopentanoate
[0314] The compound from example 6 (6.76 g, 28.8 mmol) was
initially charged and dissolved in 240 ml of dichloromethane and
9.46 ml (117 mmol, 4.05 eq) of pyridine, cooled down to 0.degree.
C. in an ice bath for 15 min and admixed with 19.86 ml of a 20%
phosgene solution in toluene (37.54 mmol, 1.3 eq) within 20-30
seconds. The mixture was stirred at 0.degree. C. for a further 2 h,
then the reaction mixture was extracted with cold half-molar HCl
and ice. The water phases were reextracted with dichloromethane,
and the combined organic phases were washed with ice and saturated
NaCl solution, then dried over MgSO.sub.4 and filtered off from the
desiccant. Concentration by evaporation under reduced pressure left
5.21 g of brown oil (corresponded to a yield of 94%), which was
reacted further directly.
Example 8
(S)-2-[(3-Azaspiro[5.5]undecane-3-carbonyl)amino]-4,4-difluoropentanoic
acid
[0315] 252 mg (1.3 mmol) of the isocyanate from example 7 were
dissolved at 0.degree. C. in 5 ml of THF and admixed with 109 mg
(3.25 mmol, 2.5 eq.) of sodium hydrogencarbonate and 209 mg (1.37
mmol, 1.05 eq.) of 3-azaspiro[5.5]undecane. The mixture was stirred
overnight, precipitated salts were removed and the reaction mixture
was treated directly with 2.5 ml of 1 M LiOH solution (2.5 mmol,
1.9 eq.). The reaction was monitored by HPLC-MS. When the mass peak
of the reactant had disappeared completely, the mixture was
acidified cautiously with dilute HCl and the product was isolated
by extraction with ethyl acetate, drying of the organic phase over
sodium sulfate and concentration under reduced pressure. Yield: 440
mg (quantitative). The crude product was used directly in the amide
coupling which follows.
Example 9
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-3-azaspiro[5.5]-
undecane-3-carboxamide
[0316] The crude product from example 8,
(S)-2-[(3-azaspiro[5.5]undecane-3-carbonyl)amino]-4,4-difluoropentanoic
acid, was dissolved in 6 ml of 2:1 THF/DMF and admixed with 161.8
mg (1.365 mmol, 1.05 eq.) of 1-amino-1-cyclopropylnitrile
hydrochloride and 176.9 mg (1.3 mmol, 1 eq.) of
1-hydroxy-7-azabenzotriazole, cooled to 0.degree. C. and admixed
with 250 mg (1.3 mmol, 1 eq.) of EDCI and with 0.496 ml (3.9 mmol,
3 eq.) of N-ethylmorpholine. Subsequently, the mixture was stirred
at 0.degree. C. to RT for 2 h, THF was distilled off under reduced
pressure, ethyl acetate was added and the mixture was extracted by
shaking with highly dilute HCl, sat. NaHCO.sub.3 solution and sat.
NaCl solution. After concentration of the organic phase, a
preparative HPLC separation (Merck Hibar Purospher RP18,
250.times.25, Standard-Gradient of acetonitrile-water-TFA) was
performed directly. Product fractions were combined and
freeze-dried.
[0317] Yield: 222 mg, 43% of theory.
[0318] .sup.1H NMR: 8.82 (s, 1H); 6.6 (s, 1H); 4.31 (m, 1H); 3.28
(about, 4H); 2.29 (m, 2H); 1.7-1.1 (m, about 20H); MS (ESI.sup.+):
397.17
Example 10
8-azaspiro[4.5]decane-8-carbonyl chloride
[0319] 1.57 ml of phosgene (20% solution in toluene, 2.96 mmol)
were initially charged in 5 ml of dichloroethane and cooled to
-20.degree. C., then a mixture of 8-azaspiro-[4,5]decane (750 mg,
2.96 mmol) and triethylamine (1.28 ml, 9.2 mmol, 3.1 eq.) was added
slowly. After 30 min, the mixture was allowed to come to RT; after
1 h, according to LC-MS, a little starting material was still
present but also three new peaks. Subsequently, the mixture was
added to 2 N aqueous HCl, the aqueous phase was extracted with
dichloromethane, and the organic phase was washed with saturated
NaHCO.sub.3 solution and dried over sodium sulfate; subsequently,
the mixture was concentrated by rotary evaporation under reduced
pressure. Crude yield: 592 mg The material was reacted further
directly without further purification. General method: see example
19.
Example 11
Benzyl (S)-4-carboxymethyl-5-oxooxazolidine-3-carboxylate
[0320] The compound is commercially available or can be prepared by
literature methods by refluxing Z-Asp-OH with paraformaldehyde on a
water separator in benzene.
Example 12
Benzyl
(S)-4-chlorocarbonylmethyl-5-oxooxazolidine-3-carboxylate
[0321] The compound from example 11 was converted analogously to
the manner described in example 1 to benzyl
(S)-4-chlorocarbonylmethyl-5-oxooxazolidine-3-carboxylate. The
product thus obtained was used without further purification in the
subsequent reaction.
Example 13
Benzyl (S)-5-oxo-4-(2-oxopropyl)oxazolidine-3-carboxylate
[0322] CuBr (24.54 g, 168 mmol, 1.2 eq.) and LiBr (29.18 g, 336
mmol, 2.4 eq.) were initially charged in a baked-out flask under
argon, then dissolved in 600 ml of absolute THF and stirred at RT
for 20 min. This gave a clear yellow-orange solution. The mixture
was then cooled to -78.degree. C., and MeMgCl solution (55.46 ml,
168 mmol, 1.2 eq.) was added dropwise thereto. This led to a yellow
suspension which was difficult to stir, so that a further 75 ml of
THF were added dropwise; the mixture was subsequently stirred at
-60.degree. C. for 15 min. The carbonyl chloride from example 12
dissolved in about 150 ml of THF (41.67 g, 140 mmol) was initially
stirred at -60.degree. C. and then slowly added dropwise. The
reaction mixture thus formed was stirred at this temperature for 1
h. The workup was effected by adding about 100 ml of saturated
NH.sub.4Cl solution; the mixture was stirred vigorously at
-60.degree. C. for 10 min, then 200 ml of heptane and 60 ml of
water were added and the mixture was stirred at RT for a further 15
min. The phases were separated, and the aqueous phase was admixed
with 50 ml of 1 M HCl (green solution) and extracted twice with
about 100 ml of ethyl acetate. The combined organic phases were
washed with 2 M HCl solution, saturated NaHCO.sub.3 and saturated
NaCl solution, dried over sodium sulfate and concentrated under
reduced pressure. Subsequently, purification was effected by means
of silica gel flash chromatography (5:1-2:1 heptane/ethyl acetate);
production fractions were combined and freed of solvent residues
under reduced pressure. Yield: 21.6 g, 56% of theory
[0323] .sup.1H NMR (250 MHz, 390 K, DMSO-d6): 7.35 (s, 5H); 5.43;
5.22 (2 d, 2H); 5.13 (d, 2H); 4.4 (dd, 1H); 3.26, 3.04 (each 2 dd,
2H); 2.07 (s, 3H).
Example 14
Benzyl
(S)-4-(2,2-difluoropropyl)-5-oxooxazolidine-3-carboxylate
[0324] 15.52 g of the compound from example 13 (56 mmol) were
suspended in 5 ml of dichloromethane and admixed with stirring with
25 g (20.8 ml, 2.02 eq.) of BAST. For 14 days, the mixture was
stirred under argon. Intermediate LC-MS spectra showed that the
conversion was not yet complete after 3 and 9 days. For workup, the
reaction solution was added dropwise to a cooled sodium
hydrogencarbonate solution (vigorous gas evolution) and stirred
further for about 30 min (no gas evolution), and the aqueous
solution was then extracted by shaking twice with DCM. The aqueous
phase was adjusted to pH 3 with dilute HCl solution and extracted
by shaking with DCM twice more. The organic phases were combined
and washed with saturated NaCl solution, dried over sodium sulfate
and concentrated by evaporation under reduced pressure. The residue
was chromatographed through silica gel with DCM/methanol (to 0-6%
methanol), and product fractions were combined and freed of solvent
residues under reduced pressure. Yield: 8 g, corresponds to 48% of
theory.
Example 15
(S)-2-Benzyloxycarbonylamino-4,4-difluoropentanoic acid
[0325] The compound from example 14 (4.9 g, 16.37 mmol) was
dissolved in 30 ml of acetone and cooled to 0.degree. C., and then
1 N sodium hydroxide solution (32.74 ml, 32.74 mmol, 2 eq.) was
added. For about 2.5 h, the reaction mixture was stirred at room
temperature; reaction monitoring by LC-MS indicated complete
conversion. This was followed by addition of 20 ml of 1 N HCl,
distilling-off of acetone under reduced pressure and adjustment of
the solution to pH 3 to 4. The mixture was extracted twice by
shaking with ethyl acetate. The organic phase was washed with
saturated NaCl solution, dried over sodium sulfate and concentrated
by evaporation to dryness under reduced pressure. The crude product
was chromatographed using silica gel with a DCM/methanol gradient
(0-6% methanol).
[0326] Yield: 4.7 g (quantitative).
Example 16
(S)-2-tert-Butoxycarbonylamino-4,4-difluoropentanoic acid
[0327] The compound from example 15 (2.99 g, 10.44 mmol) was
dissolved in 40 ml of methanol and 580 mg of 10% Pd/C were added.
Hydrogenation was effected at 2 bar for 3 h. Only a vanishingly
small Z elimination was detected. Another 300 mg of catalyst were
added and hydrogenation was effected for a further 2 h --low
conversion. The same amount of catalyst was added again and
hydrogenation was effected overnight; only then was the conversion
complete. The mixture was filtered off from the catalyst and
concentrated by evaporation. The residue was partly dissolved in
dioxane/water (40 ml), and sodium carbonate (700 mg, 0.6 eq), 10.4
ml of 1 N NaOH solution (10.4 mmol, 1 eq.) and 2.6 g of
di-tert-butyl dicarbonate (11.94 mmol, 1.14 eq.) were added. After
about 2 h, the conversion was complete. The solution was extracted
with ether and the ether phase was discarded. Subsequently, the
aqueous phase was acidified to pH 3 with 1 N HCl and extracted
twice with ethyl acetate. The organic phase was washed with a
saturated a NaCl solution, dried over sodium sulfate, filtered off
from the desiccant and concentrated by evaporation under reduced
pressure.
[0328] Yield: 950 mg, 36% of theory.
[0329] .sup.1H NMR: 12.8 (s, 1H); 7.25 (d, 1H); 4.11 (t, 1H); 2.3
(m, br., 2H); 1.6 (t, 3H); 1.37 (s, 9H).
Example 17
tert-Butyl
[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]carbamat-
e
[0330] 1.35 g (5.33 mmol) of the product from example 16, 810 mg
(6.83 mmol, 1.3 eq.) of 1-amino-1-cyclopropylnitrile hydrochloride
and 943 mg (6.93 mmol, 1.3 eq.) of HOAt were dissolved or suspended
in 18 ml of dichloromethane, cooled to 0.degree. C. and then
admixed with 1.33 g (6.93 mmol, 1.3 eq.) of EDCI and 1.76 ml (1.596
g, 13.86 mmol, 2.6 eq.) of NEM. The mixture was stirred at
0.degree. C. to RT for 16 h. The reaction mixture was then diluted
with 40 ml of DCM and extracted by shaking with 1 N HCl solution,
saturated sodium hydrogencarbonate solution and saturated NaCl
solution. The organic phase was dried over sodium sulfate and
concentrated by evaporation under reduced pressure. The product was
sufficiently clean for further reactions.
[0331] Yield: 1.5 g, 89% of theory.
Example 18
N-(1-cyanocyclopropyl)-(S)-2-amino-4,4-difluoropentanamide
[0332] To detach the Boc protecting group, the compound from
example 17 (580 mg, 1.83 mmol) was admixed with 10 ml of 1:1
TFA/DCM and stirred at RT for 30 min. Subsequently, the mixture was
concentrated by evaporation under reduced pressure and subjected to
azeotropic distillation with dichloromethane and toluene, and
solvent residues were removed under high vacuum. The product was
present as the trifluoroaceate.
[0333] Yield: 340 mg.
Example 19
General Preparation Method: Reaction of an N-Carbonyl Chloride with
C-Terminally Protected Amino Acid Units
[0334] 1 mmol of the free amino acid which has been C-terminally
protected or is present as the amide (for example the product from
example 18 after it has been released by basic treatment) was
dissolved in 10 ml of THF and cooled to 0.degree. C. The acid
chloride from example 10 (1 mmol dissolved in 5 ml of cold THF) was
then added slowly in two portions over 60 min. Subsequently, the
mixture was stirred further overnight. The reaction mixture was
added to 50 ml of dichloromethane, washed with water and saturated
NaHCO.sub.3 solution, dried over sodium sulfate and concentrated by
a rotary evaporation. The resulting oily product was subsequently
in each case purified directly by HPLC (RP-18, acetonitrile-water),
and product fractions were freeze-dried. The yields in this process
of urea formation were from about 10 to 50% of theory).
Example 20
Benzyl
(S)-5-oxo-4-(2-oxo-3-phenylpropyl)oxazolidine-3-carboxylate
[0335] Analogously to example 13, benzyl
(S)-5-oxo-4-(2-oxo-3-phenylpropyl)oxazolidine-3-carboxylate was
prepared starting from benzyl
(S)-4-chlorocarbonylmethyl-5-oxo-oxazolidine-3-carboxylate (5.00 g,
16.8 mmol) and 15 ml of a 20% benzylmagnesium chloride solution
(20.2 mmol, 1.2 eq) in THF. The product was obtained as a yellow
oil.
[0336] Yield: 5.0 g, 84% of theory.
Example 21
Benzyl
(S)-4-(2,2-difluoro-3-phenylpropyl)-5-oxooxazolidine-3-carboxylate
[0337] Analogously to example 14, benzyl
(S)-4-(2,2-difluoro-3-phenylpropyl)-5-oxo-oxazolidine-3-carboxylate
was prepared starting from benzyl
(S)-5-oxo-4-(2-oxo-3-phenylpropyl)oxazolidine-3-carboxylate (5.00
g, 14.2 mmol) and BAST (12.5 g, 56.60 mmol, 4 eq.). After
chromatography on silica gel (dichloromethane/methanol), pure
benzyl
(S)-4-(2,2-difluoro-3-phenylpropyl)-5-oxooxazolidine-3-carboxylate
was obtained in the form of a yellow oil.
[0338] Yield: 1.2 g, 23% of theory
Example 22
(S)-2-Benzyloxycarbonylamino-4,4-difluoro-5-phenylpentanoic
acid
[0339] Analogously to example 15,
(S)-2-benzyloxycarbonylamino-4,4-difluoro-5-phenylpentanoic acid
was prepared starting from benzyl
(S)-4-(2,2-difluoro-3-phenylpropyl)-5-oxooxazolidine-3-carboxylate
(1.2 g, 3.20 mmol). The product was obtained in the form of a
yellow oil which was used directly for the subsequent
reactions.
[0340] Yield: 1.02 g, 88% of theory.
Example 23
Methyl
(S)-2-benzyloxycarbonylamino-4,4-difluoro-5-phenylpentanoate
[0341] Trimethylsilyl chloride (0.61 g, 5.61 mmol, 2 eq) was added
dropwise to a solution of
(S)-2-benzyloxycarbonylamino-4,4-difluoro-5-phenylpentanoic acid
(1.02 g, 2.81 mmol) in 40 ml of methanol. After the addition had
ended, the mixture was stirred at RT for 3 h. The solvent was
removed under reduced pressure and the residue was used crude in
the reaction which followed.
[0342] Yield: 1.0 g, 94% of theory.
Example 24
Methyl (S)-2-amino-4,4-difluoro-5-phenylpentanoate
[0343] In a three-neck flask, methyl
(S)-2-benzyloxycarbonylamino-4,4-difluoro-5-phenyl-pentanoate (1.0
g, 2.65 mmol) was dissolved in 25 ml of methanol. After repeated
evacuation and sparging with argon, 350 mg of Pd/C (10%) were
added. After degassing and sparging with argon again, the argon
atmosphere was replaced by hydrogen (balloon with H.sub.2 gas). The
mixture was stirred at RT for 3 h. Owing to incomplete conversion,
a further 350 mg of catalyst were added and the mixture was
hydrogenated at RT for a further 5 h. On completion of conversion,
the reaction mixture was filtered. The mixture was washed with 20
ml of methanol and the filtrate was concentrated by evaporation
under reduced pressure. A waxy residue was obtained which, as well
as the desired product, also contained smaller amounts of the
monodefluorinated and didefluorinated product. This residue was
used without further purification for the further reaction.
[0344] Yield: 530 mg, 82% of theory.
Example 25
Methyl (S)-4,4-difluoro-2-isocyanato-5-phenylpentanoate
[0345] Under argon, methyl
(S)-2-amino-4,4-difluoro-5-phenylpentanoate (400 mg, 1.64 mmol) was
dissolved in 20 ml of dichloromethane. At RT, pyridine (520 mg, 4
eq.) was added dropwise and the resulting solution was stirred for
15 minutes. The mixture was then cooled to 0.degree. C. and admixed
with 20% phosgene solution in toluene (2.16 ml, 4.1 mmol, 2.5 eq.).
The mixture was stirred at RT for 90 minutes and then the solvent
was removed under reduced pressure. The mixture was codistilled
with 10 ml of toluene twice more. The crude product thus obtained
was used for the reactions which followed without further
purification.
[0346] Yield: 425 mg, 96% of theory
Example 26
Methyl
(S)-2-[(8-azaspiro[4.5]decane-8-carbonyl)amino]-4,4-difluoro-5-phen-
ylpentanoate
[0347] Methyl (S)-4,4-difluoro-2-isocyanato-5-phenylpentanoate (425
mg, 1.58 mmol) were dissolved in 25 ml of dichloromethane.
8-Azaspiro[4.5]decane (220 mg, 1.58 mmol, 1 eq.) and DIPEA (269
.mu.l, 204 mg, 1.58 mmol, 1 eq.) were added to this solution which
was stirred at RT overnight. The solvent was removed under reduced
pressure and the residue was purified by preparative HPLC
(gradient: acetonitrile/water and addition of 0.05% TFA). The
product-containing fractions were combined and freed from the
solvent under reduced pressure.
[0348] Yield: 245 mg, 38% of theory.
Example 27
(S)-2-[(8-Azaspiro[4.5]decane-8-carbonyl)amino]-4,4-difluoro-5-phenyl-pent-
anoic acid
[0349] Methyl
(S)-2-[(8-azaspiro[4.5]decane-8-carbonyl)amino]-4,4-difluoro-5-phenylpent-
anoate (240 mg, 0.59 mmol) was dissolved in a mixture of 15 ml of
THF and 5 ml of methanol. A solution of 42 mg of LiOH (1.76 mmol, 3
eq.) in 5 ml of water was added and the mixture was stirred at RT
for 3 h. After the reaction had ended, the reaction mixture was
acidified to pH=3 by adding a 2 M HCl solution. The organic solvent
was removed under reduced pressure and the remaining aqueous phase
was extracted with ethyl acetate. Subsequently, the organic phase
was washed another three times with water and once with saturated
NaCl solution, dried over MgSO.sub.4 and freed from the solvent
under reduced pressure. The product was obtained in the form of a
yellow solid which was used in the reaction which followed without
further purification.
[0350] Yield: 192 mg, 82% of theory.
Example 28
N--[(S)-1-(1-Cyanocyclopropylcarbamoyl)-3,3-difluoro-4-phenylbutyl]-8-azas-
piro[4.5]decane-8-carboxamide
[0351] DIPEA (331 .mu.l, 252 mg, 1.95 mmol, 4 eq.), HATU (185 mg,
0.49 mmol, 1 eq.) and 1-aminocyclopropanecarbonitrile hydrochloride
(58 mg, 0.49 mmol, 1 eq.) were added successively to a solution of
the
(S)-2-[(8-azaspiro[4.5]decane-8-carbonyl)amino]-4,4-difluoro-5-phenylpent-
anoic acid obtained as a crude product (192 mg, 0.49 mmol) in 10 ml
of DMF. The reaction mixture was stirred at RT overnight and, the
next day, concentrated under reduced pressure. The residue thus
obtained was purified by preparative HPLC (gradient:
acetonitrile/water and addition of 0.05% TFA). The title compound
was obtained in the form of a colorless crystalline material.
[0352] Yield: 34 mg, 15% of theory.
[0353] .sup.1H NMR: 8.83 (s, 1H); 7.48-7.15 (m, 5H); 6.62 (s, 1H);
4.39 (m, 1H); 3.30-3.15 (m, 6H); 2.39 (m, 1H); 2.22 (m, 1H);
1.65-1.05 (m, about 16H); MS (ESI.sup.+): 459.2
Example 29
[0354] tert-Butyl
9-cyclopropyl-3,9-diazaspiro[5.5]undecane-3-carboxylate tert-Butyl
3,9-diazaspiro[5.5]undecane-3-carboxylate (250 mg, 0.98 mmol) were
dissolved in 10 ml of absolute methanol. 3 g of molecular sieves (3
.ANG., which had been dried beforehand under high vacuum) were
added to this solution. Under argon, glacial acetic acid (0.55 ml,
10 eq.), [(1-ethoxycyclopropyl)oxy]trimethylsilane (0.69 ml, 3.5
eq.) and 4.4 ml of a 1 M NaCNBH.sub.3 solution in THF (4.4 mmol,
4.5 eq.) were then added successively. After stirring at RT for 20
minutes, the mixture was heated to 60.degree. C. and stirred at
this temperature for about 15 h. The reaction mixture was filtered
and the filtrate was concentrated under reduced pressure. The
residue was taken up in dichloromethane, washed successively with 1
M NaOH solution and NaCl solution, and dried over MgSO.sub.4. After
the solvent had been removed under reduced pressure, the product
was obtained as a colorless oil.
[0355] Yield: 318 mg (quant.)
Example 30
3-Cyclopropyl-3,9-diazaspiro[5.5]undecane
[0356] The tert-butyl
9-cyclopropyl-3,9-diazaspiro[5.5]undecane-3-carboxylate obtained as
a crude product (318 mg, 0.98 mmol) was dissolved in 6 ml of
dichloromethane and admixed with 1 ml of a 4 M HCl solution in
dioxane (4 mmol, 4 eq.) with ice bath cooling. The mixture was
stirred at RT for about 16 h. The solvent was evaporated under
reduced pressure. The residue was taken up in 20 ml of water and
lyophilized. Thus, 3-cyclopropyl-3,9-diazaspiro[5.5]undecane
hydrochloride was obtained as a crude product in the form of a
colorless amorphous material which was clean enough for further
reactions.
[0357] Yield: 252 mg, quantitative.
[0358] The piperidine derivative thus obtained was converted to the
end products, which are listed in table 1a and 1b, as in the
above-described examples.
Example 31
[0359] tert-Butyl 9-butyl-3,9-diazaspiro[5.5]undecane-3-carboxylate
tert-Butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (150 mg, 0.59
mmol) was dissolved in 10 ml of absolute dichloromethane and
admixed with butyraldehyde (52 .mu.l, 1 eq.). With ice bath
cooling, 17 .mu.l of glacial acetic acid (0.5 eq.) and sodium
triacetoxyborohydride (137 mg, 1.1 eq.) were added. The mixture was
stirred at RT for 16 h. Owing to incomplete reaction, butyraldehyde
(52 .mu.l, 1 eq.), glacial acetic acid (17 .mu.l, 0.5 eq.) and
sodium triacetoxyborohydride (137 mg, 1.1 eq.) were again added.
After stirring at RT for a further 4 h, a little water was added
and the reaction mixture was washed with saturated NH.sub.4Cl
solution. The organic phase was dried over MgSO.sub.4 and freed
from the solvent under reduced pressure. The product was obtained
as a colorless oil.
[0360] Yield: 211 mg (quant.)
Example 32
3-Butyl-3,9-diazaspiro[5.5]undecane
[0361] The tert-butyl
9-butyl-3,9-diazaspiro[5.5]undecane-3-carboxylate obtained as a
crude product (183 mg, 0.59 mmol) was dissolved in 4 ml of
dichloromethane and admixed with 0.6 ml of a 4 M HCl solution in
dioxane (2.4 mmol, 4 eq.) with ice bath cooling. The mixture was
stirred at RT for about 16 h. The solvent was removed under reduced
pressure. The residue was taken up in 20 ml of water and
lyophilized. Thus, 3-butyl-3,9-diazaspiro[5.5]undecane
hydrochloride was obtained as a crude product in the form of a
colorless amorphous material which was clean enough for further
reactions. Yield: 176 mg, quantitative.
[0362] The piperidine derivative thus obtained was converted to the
end products, which are listed in table 1a and 1b, as in the
above-described examples.
Example 33
1,4-Dioxaspiro[4.5]decane-8-carboxylic acid
[0363] 3.0 g (14 mmol) of the ethyl ester precursor, ethyl
1,4-dioxaspiro[4.5]decane-8-carboxylate, were dissolved in 5 ml of
methanol and admixed at RT slowly with 28 ml (2 eq.) of 1 M LiOH
solution. The mixture was stirred overnight; HPLC-MS indicated
complete reaction. Methanol was distilled off under reduced
pressure and the residue was acidified cautiously with 1 ml of HCl
such that no acid excess was present. The mixture was extracted
with ethyl acetate, and the ethyl acetate phase was dried over
sodium sulfate and then concentrated by evaporation under reduced
pressure. Yield: 2.25 g, 86% of theory.
Example 34
tert-Butyl
[(S)-1-(1-cyanocyclopropylcarbamoyl)-3-methylbutyl]carbamate
[0364] 5 g of Boc-(S)-Leu-OH (21.6 mmol), 3.3 g of
1-aminocyclopropanecarbonitrile hydrochloride (28.1 mmol, 1.3 eq.)
and 3.8 g of HOBt (28.1 mmol, 1.3 eq.) were suspended in 60 ml of
dichloromethane and admixed at 0.degree. C. successively with 5.4 g
of EDCI (28.1 mmol, 1.3 eq.) and 7.15 ml of NEM (6.5 g, 56.2 mmol,
2.6 eq.). The mixture was stirred at 0.degree. C. to RT overnight,
extracted by shaking under acidic (1 M HCl solution), basic
(saturated NaHCO.sub.3 solution) and neutral (saturated NaCl
solution) conditions, and dried over sodium sulfate, and the
solvent was distilled off under reduced pressure. The mixture was
then chromatographed on silica gel in ethyl acetate/heptane. Yield:
3.62 g, 57% of theory.
[0365] .sup.1H NMR: 8.82 (s, 1H); 6.92 (d, 1H); 3.86 (m, 1H); 1.55
(m, 1H); 1.47 (m, 2H); 1.36 (s, 9H); 1.09 (m, 2H); 0.86 (dd, 6H);
MS (ESI.sup.+): 296.3.
Example 35
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3-methylbutyl]-1,4-dioxaspiro[4.5]-
decane-8-carboxamide
[0366] The product from example 34, tert-butyl
[(S)-1-(1-cyanocyclopropylcarbamoyl)-3-methylbutyl]carbamate, (1.1
g, 3.72 mmol) was admixed with 20 ml of 1:1
[0367] TFA/dichloromethane and stirred at RT for 30 min.
Subsequently, the mixture was concentrated by evaporation under
reduced pressure and taken up again in dichloromethane and toluene,
and solvent and TFA residues were removed under reduced pressure.
The resulting N-terminally protected product was reacted further
directly. 283 mg (1.5 mmol) thereof were admixed at 0.degree. C.
with 136 mg of HOAt (1 mmol, 0.67 eq.), 195 mg of
1,4-dioxaspiro[4.5]decane-8-carboxylic acid from example 33 (1
mmol, 0.67 eq.), 268 mg of EDCI (1.4 mmol, 0.93 eq.) and 0.32 ml of
NEM (2.5 mmol) in 2.5 ml of THF and 0.25 ml of DMF, and the mixture
was stirred at 0.degree. C. to RT overnight. Subsequently, the
solvent was distilled off under reduced pressure, and the residue
was taken up in ethyl acetate and extracted by shaking with
saturated sodium hydrogencarbonate solution and saturated NaCl
solution. Drying over sodium sulfate and evaporating-off the
solvent were followed by purification using RP-HPLC (gradient:
acetonitrile/water and addition of 0.05% TFA). The product
fractions were combined and freeze-dried. Yield: 25 mg (without
mixed fractions), corresponds to 7% of theory. .sup.1H NMR: 8.81
(s, 1H); 7.84 (d, 1H); 4.20 (m, 1H); 3.83 (s, 4H); 2.22 (m, 1H);
1.75-0.8 (3m, about 13H, 1.05 (m, 2H); 0.82 (dd, 6H); MS
(ESI.sup.+): 364.2. The examples listed in table 1a were prepared
in a manner analogous to that described above. Table 1a shows the
examples with accompanying characterization:
TABLE-US-00001 TABLE 1a Molar mass (parent MS Ex. compound)
Structure (ESI.sup.+) .sup.1H NMR 36 382.46 ##STR00048## 383.1 8.82
(s, 1H); 6.62 (d, 1H); 4.28 (m, 1H); 3.29 (m, 4H); 2.26 (m, 2H);
1.65-1.05 (mm, 19 H) 37 386.4 ##STR00049## 387.1 8.83 (s, 1); 6.80
(d, 1H); 4.30 (m, 1H); 3.6 (m, 1H); 3.4 (m, approx, 4 H); 2.25 (m,
approx, 4H); 1.7- 1.4 (mm, approx, 11H); 1.1 (m, 2H) 38 396.48
##STR00050## 397.1 8.81 (s, 1H); 6.6 (d, 1H); 4.3 (m, 1H); 3.3 (m,
2H); 3.15 (dd, 2H); 2.29 (m, 2H); 1.6-1.0 (mm, approx. 20H) 39
410.51 ##STR00051## 411.5 8.82 (s, 1H); 6.62 (d, 1H); 4.28 (m, 1H);
3.29 (m, 4H); 2.26 (m, 2H); 1.82 (m, 2H); 1.65-1.05 (mm, approx.
18H); 0.88 (t, 3H) 40 424.54 ##STR00052## 425.6 8.82 (s, 1H); 6.62
(d, 1H);4.28 (m, 1H); 3.29 (m, 4H); 2.26 (m, 2H); 1.60-1.05 (mm,
approx. 20H); 0.88 (t, 3H) 41 503.55 ##STR00053## 504.2 9 (s, 1H);
7.58 (d, 2H); 6.93 (d, 2H); 6.82 (d, 1H); 4.31 8 m, 1H); 3.92 (m,
2H); 3.77 (m, 2H); 3.76 (s, 3H); 2.92 (m, 2H); 2.30 (m, 2H); 2.07
(m, 2H); 1.69-1.4 (2 m, 9H); 1.1 (m, 2H) 42 474.51 ##STR00054##
475.3 8.94 (s, 1H); 8.88 (s, 1H); 7.4 (t, 2H); 6.87 (d, 1H); 6.7
(m, 3H); 4.6 (s, 2H); 4.39 (m, 1H); 3.96 (m, 2H); 2.6-2.2 (m, br,
approx, 6H); 1.6 (m, br, approx, 7H); 1.11 (m, 2H) 43 397.43
##STR00055## 398.4 8.88 (s, 1H); 7.57 (s, 1H); 6.72 (d, 1H); 4.28
(m, 1H); 3.85 (m, 2H); 3.2 (t, 2H); 2.88 (m, 2H); 2.3 (m, 2H); 1.92
(m, 2H); 1.65-1.4 (m, br, 7H); 1.29 (m, 2H); 1.1 (m, 2H) 44 411.46
##STR00056## 412.5 8.88 (s, 1H); 6.72 (d, 1H); 4.28 (m, 1H); 3.85
(m, 2H); 3.28 (t, 2H): 2.88 (m, 2H); 2.7 (s, 3H); 2.3 (m, 2H); 1.92
(m, 2H); 1.65-1.4 (m, br, 7H); 1.29 (m, 2H); 1.1 (m, 2H) 45 427.5
##STR00057## 429.5 8.85 (s, 1H); 6.75 (d, 1H); 4.29 (m, 1H); 3.6
(s, 1H, overl, water); 3.46 (s, 4H); 3.3 (m, 4H); 2.3 (m, 2H);
1.73-1.42 (3 m, 9H); 1.1 (m, 2H); 0.88 (s, 6H) 46 430.5
##STR00058## 431.2 8.89 (s, 1H); 7.15 (m, 4H); 6.74 (d, 1H); 4.34
(m, 1H); 3.98 (dd, 2H); 2.9 (m, 4H); 2.3 (m, 2H); 2.0 (m, 2H); 1.65
(m, 5H); 1.45 (m, 4H); 1.1 (m, 2H) 47 412.4 ##STR00059## 413.4 8.88
(s, 1H); 8.51 (s, 1H); 6.8 (d, 1H); 4.3 (m, 1H); 3.1 (m, 2H);
2.8-2.1 (m, br, approx. 6H); 1.6 (m, br, approx. 5H); 1.24; 1.11 (2
m, 4H) 48 368.43 ##STR00060## 369.3 8.88 (s, 1H); 6.24 (d, 1H); 4.3
(m, 1H); 3.3 (m, 2H); 3.1 (dd, 2H); 2.3 (m, 1H); 1.75-0.9 (mm,
15H); 1.1 (m, 2H) 49 487.55 ##STR00061## 488.5 8.88 (s, 1H); 7.4-
7.15 (3 m, 5H); 6.74 (d, 1H); 4.39 (s, 2H); 4.3 (m, 1H); 3.9 (dd,
2H); 3.18 (m, 2H); 2.9 (dt, 2H); 2.3 (m, 2H); 1.7-1.3 (3 m, 6H);
1.1 (m, 1H) 50 491.52 ##STR00062## 492.5 8.89 (s, 1H); 7.68 (m,
2H); 7.20 (m, 2H); 6.78 (d, 1H); 4.31 8 m, 1H); 3.92 (m, 2H); 3.77
(m, 2H); 2.92 (m, 2H): 2.30 (m, 2H); 2.07 (m, 2H); 1.7-1.4 (2 m,
9H); 1.1 (m, 2H) 51 400.43 ##STR00063## 401.3 8.82 (s, 1H); 6.72
(d, 1H); 4.28 (m, 1H); 3.83 (m, 4H); 3.3 (m, approx. 4H, water
overlap); 2.28 (m, 2H); 1.75-1.4 (3 m, approx. 11H); 1.1 (m, 2H) 52
476.53 ##STR00064## 477.4 8.86 (s, 1H); 7.31 (s, 5H); 6.8 (d, 1H);
4.30 (m, 1H); 4.0 (m, 2H); 3.9 (m, 2H); 3.4 (m, approx. 5H, overlap
water); 3.05 (m, 1H); 2.28 (m, 2H); 2.0 (m, 2H); 1.7-1.3 (2 m,
approx. 7H): 1.1 (m, 2H) 53 372.51 ##STR00065## 373.2 8.26 (s, 1H);
5.83 (s, 1H); 3.26 (m, approx, 5H); 1.9-1.0 (mm, approx. 25 H) 54
386.54 ##STR00066## 387.2 8.83 (s, 1H); 6.20 (m, 1H); 3.9, 3.8 (2t,
1H); 3.28 (m, 4H); 1.75-0.8 (mm, approx. 27H) 55 453.29
##STR00067## 454.3 8.86 (s, 1H); 6.68 (d, 1H); 4.29 (m, 1H); 3.3
(m, 6H); 3.0 (m, 4H); 2.28 (m, 2H); 1.81 (m, 2H); 1.65- 1.4 (m,
11H); 1.3 (m, 4H); 1.1 (m, 2H); 0.9 (t, 3H) 56 437.26 ##STR00068##
438.2 8.89 (s, 1H); 6.7 (d, 1H); 4.28 (m, 1H); 3.32 (m, approx. 8H,
water overlap); 2.89 (m, 1H); 2.26 (m, 2H); 1.83 ("d", 2H);
1.66-1.37 (m, 2 m, 9H); 1.28 (m, 2H); 1.1 (m, 2H); 0.85 (2 m, 4H)
57 303.41 ##STR00069## 302.4 (ES.sup.-) 8.89 (s, 1H); 8.1 (d, 1H);
4.18 (m, 1H); 2.0 (m, br, approx. 5H); 1.66-1.32 (m mm, approx.
6H); 1.07 (m, 2H); 0.94- 0.74 (m, dd, approx. 10H)
[0368] Further spirocyclic amines which have been used hereinafter
for the preparation of further inventive examples were prepared as
follows: the spirocyclic amines
7-cyclo-propyl-2,7-diazaspiro[3.5]-nonane,
7-propyl-2,7-diazaspiro[3.5]nonane,
2-cyclopropyl-2,8-diazaspiro[4.5]decane,
2-cyclopropyl-2,7-diazaspiro[3.5]nonane,
2-propyl-2,7-diazaspiro[3.5]nonane,
9-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecane and
4-cyclo-propyl-1-oxa-4,9-diazaspiro[5.5]undecane were prepared
according to the above-described examples 29-32 starting from the
tert-butyloxycarbonyl-protected precursors which are commercially
available. 2-Cyclopropylmethyl-2,8-diazaspiro[4.5]decan-3-one was
obtained by alkylating tert-butyl
3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (commercially
available) with cyclopropylmethyl bromide and subsequent
elimination of the tert-butyloxycarbonyl protecting group with TFA.
6-Azaspiro[2.5]octane can be prepared according to the literature
(Bull. Soc Chim. France 10, 2572-81 (1964)) or else as described
below by cyclopropanating tert-butyl
4-methylenepiperidine-1-carboxylate and then detaching the
tert-butyloxycarbonyl protecting group.
Example 58
6-Azaspiro[2.5]octane
##STR00070##
[0370] In a baked-out dry flask under protective gas (argon), a
mixture of 9.90 g of zinc dust (151 mmol) and 1.50 g of CuCl (15.15
mmol) in 20 ml of abs. diethyl ether was stirred at 50.degree. C.
(bath temperature) for approx. 100 min. The mixture was cooled to
15.degree. C. (bath temperature). 6.1 ml of diiodomethane (75.0
mmol), 7.8 ml of abs. dimethoxyethane and finally 4.27 g of
tert-butyl 4-methylenepiperidine-1-carboxylate (21.7 mmol) were
successively and rapidly added dropwise. The reaction mixture was
heated gradually to 50.degree. C. (bath temperature) and stirred at
this temperature for approx. 20 h. After this time, owing to still
incomplete conversion, another 20 ml of diethyl ether and 6.1 ml of
diiodomethane were added with cooling. The reaction mixture was
heated to 50.degree. C. (bath temperature) for a further 8 h.
Cooling was followed by dilution with THF and filtration through
Celite. The filtrate was admixed with 4.3 g of p-toluenesulfonic
acid and a few drops of water, and then concentrated under reduced
pressure. The crude product thus obtained was dissolved in 100 ml
of THF and admixed with 7.09 g of Boc anhydride (1.5 eq.) and 5.5
ml of DIPEA (1.5 eq.). The mixture was stirred at RT for 48 h and
then concentrated under reduced pressure. The residue thus obtained
was stirred with approx. 150 ml of diethyl ether. The mixture was
filtered with suction and the filter residue was washed thoroughly
with diethyl ether. The filtrate thus obtained was concentrated.
What remained was an oil which was taken up in 200 ml of
dichloromethane and was washed twice with sat. NaHCO.sub.3 solution
and once with dil. HCl solution (pH=5). The organic phase was dried
over MgSO.sub.4 and then concentrated under reduced pressure. In
this way, 2.8 g of tert-butyl 6-azaspiro[2.5]octane-6-carboxylate
were obtained as a light-colored oil. This oil was dissolved in 5
ml of dichloromethane and admixed with a mixture of 10 ml of TFA
and 0.5 ml of water. After stirring at RT for 48 h, the reaction
solution was concentrated under reduced pressure and codistilled
with toluene three times more. In this way, 6-azaspiro[2.5]octane
was obtained as a TFA salt in the form of a brown oil which was
clean enough for further reactions.
[0371] Yield: 1.50 g (31% of theory) MS (ESI.sup.+): 112.
[0372] The 6-azaspiro[2.5]octane thus obtained was converted to the
inventive compounds which have been described in examples 61-63 and
68-70.
Example 59
Methyl (S)-2-amino-4,4-difluoropentanoate hydrochloride
##STR00071##
[0374] At approx. 5.degree. C. (ice bath cooling), 8.2 ml of
thionyl chloride (112.6 mmol; 1.5 eq.) were added dropwise to 100
ml of methanol (p.a.) under argon. The mixture was allowed to come
to RT within 30 min and stirred for a further 30 min. 19.0 g of
(S)-2-tert-butoxycarbonylamino-4,4-difluoropentanoic acid (75.0
mmol) were added in portions to this reaction mixture. The reaction
mixture was stirred at RT for 2 h. Thereafter, the reaction mixture
was warmed to 35.degree. C. (internal temperature) and stirred at
this temperature for another 3 h. Subsequently, the mixture was
concentrated under reduced pressure, which afforded methyl
(S)-2-amino-4,4-difluoropentanoate hydrochloride as a slightly
brownish crystalline solid which was clean enough for further
reactions. Yield: 13.5 g (89% of theory).
Example 60
Methyl (S)-4,4-difluoro-2-isocyanatopentanoate
##STR00072##
[0376] Under argon, 2.0 g of methyl
(S)-2-amino-4,4-difluoropentanoate hydrochloride (9.8 mmol) were
dissolved in 80 ml of dichloromethane, admixed with 3.2 ml of
pyridine (4 eq.) and cooled to approx. 5.degree. C. (ice bath).
After 10 min, 6.7 ml (1.3 eq.) of a 20% phosgene solution in
toluene were slowly added dropwise. The resulting suspension was
stirred with ice bath cooling for 3 h and then concentrated under
reduced pressure.
[0377] The residue thus obtained was taken up in toluene and
filtered. After the solvent had been removed under reduced
pressure, methyl (S)-4,4-difluoro-2-isocyanatopentanoate was
obtained as a brown oil which was used in the subsequent reaction
without further purification. Yield: 1.1 g (58% of theory).
Example 61
Methyl
(S)-2-[(6-azaspiro[2.5]octane-6-carbonyl)amino]-4,4-difluoropentano-
ate
##STR00073##
[0379] A solution of 0.75 g of 6-azaspiro[2.5]octane
trifluoroacetate (3.30 mmol, 1 eq.) and 0.75 ml of DIPEA (1.3 eq.)
in 6 ml of dichloroethane was added under argon to a solution of
0.65 g of methyl (S)-4,4-difluoro-2-isocyanatopentanoate (3.36
mmol) in 4 ml of dichloroethane. The reaction mixture was stirred
at RT overnight. The mixture was diluted with 10 ml of
dichloromethane and washed with saturated NaHCO.sub.3 solution. The
organic phase was dried over MgSO.sub.4 and then concentrated under
reduced pressure. The residue thus obtained was purified by
preparative HPLC (gradient: acetonitrile/water and addition of
0.05% TFA. The product-containing fractions were combined and
freeze-dried.
[0380] Yield: 200 mg, 20% of theory MS (ESI.sup.+): 305.
Example 62
(S)-2-[(6-Azaspiro[2.5]octane-6-carbonyl)amino]-4,4-difluoropentanoic
acid
##STR00074##
[0382] 365.0 mg of methyl
(S)-2-[(6-azaspiro[2.5]octane-6-carbonyl)amino]-4,4-difluoropentanoate
(1.2 mmol) were dissolved in a mixture of 10.8 ml of THF and 3.6 ml
of methanol. 3.6 ml of an aqueous 1 M LiOH solution (3 eq.) were
added to this solution. The mixture was stirred at 45.degree. C.
(bath temperature) for one hour and then 3.6 ml of 1 M HCl solution
were added. The mixture was concentrated under reduced pressure and
codistilled with DMF twice more. The
(S)-2-[(6-azaspiro[2.5]octane-6-carbonyl)amino]-4,4-difluoropentanoic
acid thus obtained was clean enough for the next reaction. Yield:
400 mg (quant.)
Example 63
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-6-azaspiro[2.5]-
octane-6-carboxamide
##STR00075##
[0384] 142.3 mg of 1-aminocyclopropanecarbonitrile hydrochloride
(1.2 mmol, 1.0 eq.), 163.3 mg of HOAt (1.0 eq.), 0.61 ml of DIPEA
(3 eq.) and 456 mg of HATU (1.0 eq.) were added successively to a
solution of 348.0 mg of
(S)-2-[(6-azaspiro[2.5]octane-6-carbonyl)amino]-4,4-difluoropentano-
ic acid (1.2 mmol) in 5 ml of DMF. The reaction mixture was stirred
at RT for 24 h and then concentrated under reduced pressure. The
residue was taken up in 10 ml of dichloromethane, washed with a
little sat. NaHCO.sub.3 solution and then a little dilute HCl
solution (pH=5), and dried over MgSO.sub.4. The residue thus
obtained was purified by preparative HPLC (gradient:
acetonitrile/water and addition of 0.05% TFA). The
product-containing fractions were combined and freeze-dried. In
this way,
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-6-az-
aspiro[2.5]octane-6-carboxamide was obtained as a colorless
amorphous solid.
[0385] Yield: 200 mg, 47% of theory. MS (ESI.sup.+): 355.1.
[0386] .sup.1H NMR: 8.85 (s, 1H); 6.68 (d, 1H); 4.30 (m, 1H);
3.30-3.40 (m, 4H); 2.30 (m, 2H); 1.60 (t, 3H); 1.50 (m, 2H); 1.25
(m, 4H); 1.10 (m, 2H); 0.30 (s, 4H).
Example 64
Methyl (S)-2-benzyloxycarbonylamino-4-oxo-5-phenylpentanoate
##STR00076##
[0388] In a baked-out, argon-purged flask, 3.7 g of lithium bromide
(2.4 eq.) and 4.38 g (1.2 eq) of CuBr-Me.sub.2S were dissolved in
55 ml of abs. THF and stirred at RT for 20 min. The resulting
yellow solution was cooled to -70.degree. C. and admixed with 16.2
ml (1.2 eq.) of benzylmagnesium chloride solution (20% in THF).
After a further 20 min at -70.degree. C., a solution of 5.32 g of
methyl (S)-2-benzyloxycarbonylamino-3-chlorocarbonylpropionoate
(example 1) (17.75 mmol) in 15 ml of THF was added. After 2 h, the
mixture was heated slowly to -35.degree. C. and 50 ml of a sat.
NH.sub.4Cl solution were added. The reaction mixture was diluted
with 400 ml of dichloromethane and washed with 100 ml of a 2 M HCl
solution. The aqueous phase was washed twice more with 50 ml of
dichloromethane. The combined organic phases were washed
successively with 2 M HCl solution, sat. NaHCO.sub.3 solution and
sat. NaCl solution, dried over MgSO.sub.4 and concentrated under
reduced pressure. Methyl
(S)-2-benzyloxycarbonylamino-4-oxo-5-phenylpentanoate was obtained
as a yellow oil which was used in the next stage without further
purification.
[0389] Yield: 6.39 g (quant.)
Example 65
Methyl
(S)-2-benzyloxycarbonylamino-4,4-difluoro-5-phenylpentanoate
##STR00077##
[0391] In a Teflon vessel, 6.3 g of methyl
(S)-2-benzyloxycarbonylamino-4-oxo-5-phenylpentanoate (17.7 mmol)
were dissolved in 10 ml of dichloromethane. Under argon, 5 g of
BAST (1.28 eq.) were added. The reaction mixture was stirred at
40.degree. C. (bath temperature) for 20 h. Another 5 g of BAST
(1.28 eq.) were added and the mixture was stirred at 40.degree. C.
for a further 20 h. The reaction mixture was added dropwise to 500
ml of an ice-cooled NaHCO.sub.3 solution and diluted with 200 ml of
dichloromethane. The phases were separated and the aqueous phase
was washed twice with 100 ml of dichloromethane. The combined
organic phases were washed with a 1 M HCl solution and with sat.
NaCl solution, dried over MgSO.sub.4 and concentrated under reduced
pressure. The residue (dark brown oil) was purified by flash
chromatography on silica gel with a heptane/ethyl acetate mixture.
Methyl (S)-2-benzyloxycarbonylamino-4,4-difluoro-5-phenylpentanoate
was obtained as a yellow waxy substance.
[0392] Yield: 3.03 g (45% of theory).
Example 66
Methyl (S)-2-amino-4,4-difluoro-5-phenylpentanoate
##STR00078##
[0394] 3.0 g of methyl
(S)-2-benzyloxycarbonylamino-4,4-difluoro-5-phenylpentanoate (8.0
mmol) were admixed with 8.0 ml (5 eq.) of a 30% HBr solution in
glacial acetic acid with ice bath cooling and stirred for 3 h. 100
ml of diethyl ether were added and the resulting precipitate was
filtered off with suction. The crude product thus obtained was
purified by preparative HPLC (gradient: acetonitrile/water and
addition of 0.05% TFA). The amorphous solid obtained after
freeze-drying was taken up in dichloromethane and washed with sat.
NaHCO.sub.3 solution. The organic phase was dried over MgSO.sub.4
and concentrated under reduced pressure. Thus, methyl
(S)-2-amino-4,4-difluoro-5-phenyl-pentanoate was obtained as a
yellow oil.
[0395] Yield: 817 mg (42% of theory)
Example 67
Methyl (S)-4,4-difluoro-2-isocyanato-5-phenylpentanoate
##STR00079##
[0397] 817 mg of methyl (S)-2-amino-4,4-difluoro-5-phenylpentanoate
(3.36 mmol) were dissolved in 20 ml of dichloromethane, admixed
with 1.08 ml of pyridine (4 eq.) and cooled to approx. 5.degree. C.
(ice bath). After 10 min, 2.3 ml (1.3 eq.) of a 20% phosgene
solution in toluene were added dropwise. The resulting suspension
was stirred with ice bath cooling for 4 h and then concentrated
under reduced pressure. The residue thus obtained was taken up in
toluene and filtered. After the solvent had been removed under
reduced pressure, methyl
(S)-4,4-difluoro-2-isocyanato-5-phenylpentanoate was obtained as an
orange oil which was used without further purification in the
subsequent reaction. Yield: 943 mg (quant.)
Example 68
Methyl
(S)-2-[(6-azaspiro[2.5]octane-6-carbonyl)amino]-4,4-difluoro-5-phen-
ylpentanoate
##STR00080##
[0399] Methyl
(S)-2-[(6-azaspiro[2.5]octane-6-carbonyl)amino]-4,4-difluoro-5-phenylpent-
anoate was prepared analogously to example 61, starting from 904 mg
of methyl (S)-4,4-difluoro-2-isocyanato-5-phenylpentanoate (3.36
mmol) and 907 mg of 6-azaspiro[2.5]octane trifluoroacetate (1.2
eq.). Chromatographic separation by preparative HPLC (gradient:
acetonitrile/water and addition of 0.05% TFA) gave methyl
(S)-2-[(6-azaspiro[2.5]octane-6-carbonyl)amino]-4,4-difluoro-5-phenylpent-
anoate as a yellow oil. Yield: 234 mg (18% of theory)
Example 69
(S)-2-[(6-Azaspiro[2.5]octane-6-carbonyl)amino]-4,4-difluoro-5-phenylpenta-
noic acid
##STR00081##
[0401]
(S)-2-[(6-Azaspiro[2.5]octane-6-carbonyl)amino]-4,4-difluoro-5-phen-
ylpentanoic acid was prepared analogously to example 62, starting
from 234 mg of methyl
(S)-2-[(6-azaspiro[2.5]octane-6-carbonyl)amino]-4,4-difluoro-5-phenylpent-
anoate (0.62 mmol). Chromatographic separation by preparative HPLC
(gradient: acetonitrile/water and addition of 0.05% TFA) gave
(S)-2-[(6-azaspiro[2.5]octane-6-carbonyl)amino]-4,4-difluoro-5-phenylpent-
anoic acid as a colorless amorphous solid.
[0402] Yield: 41 mg (18% of theory).
Example 70
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-phenylbutyl]-6-azas-
piro[2.5]octane-6-carboxamide
##STR00082##
[0404] 13.3 mg of 1-aminocyclopropanecarbonitrile hydrochloride
(1.0 eq.), 15.2 mg of HOAt (1.0 eq.), 57 .mu.l of DIPEA (3 eq.) and
42.5 mg of HATU (1.0 eq.) were added successively to a solution of
41.0 mg of
(S)-2-[(6-azaspiro[2.5]octane-6-carbonyl)amino]-4,4-difluoro-5-phenylpent-
anoic acid (0.11 mmol) in 5 ml of DMF. The reaction mixture was
stirred at RT for 4 h and then concentrated under reduced pressure.
The residue thus obtained was purified by preparative HPLC
(gradient: acetonitrile/water and addition of 0.05% TFA). The
product-containing fractions were combined and freeze-dried. In
this way,
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-phenylbutyl]-6-aza-
spiro[2.5]octane-6-carboxamide was obtained as a colorless
amorphous solid.
[0405] Yield: 30 mg, 62% of theory.
[0406] .sup.1H NMR: 8.85 (s, 1H); 7.22-7.40 (m, 5H); 6.68 (d, 1H);
4.40 (m, 1H); 3.20-3.40 (m, 6H); 2.15-2.40 (m, 2H); 1.48 (d, 2H);
1.25 (t, 4H); 1.10 (d, 2H); 0.30 (s, 4H);
[0407] MS (ESI.sup.+): 431.3.
Example 71
8-Azaspiro[4.5]decane-8-sulfonyl chloride
##STR00083##
[0409] 1.0 g of 8-azaspiro[4.5]decane (7.2 mmol) were dissolved in
25 ml of dichloromethane. After addition of 1.5 ml of triethylamine
(1.5 eq.), the mixture was cooled to 0.degree. C. At this
temperature, a solution of 0.48 ml of chorosulfonic acid (7.2 mmol,
1 eq.) in 5 ml of dichloromethane and then 1.9 ml of pyridine (3.2
eq.) were added. The mixture was stirred at RT for 48 h. The
reaction mixture was washed with a 1 M HCl solution and the aqueous
phase was removed. Thereafter, the organic phase was shaken with an
Na.sub.2CO.sub.3 solution. The aqueous phase thus obtained was then
washed three times more with a little diethyl ether. The aqueous
phase was concentrated under reduced pressure and codistilled three
times more with 20 ml of toluene each time. The residue was taken
up in water and lyophilized. The colorless residue thus obtained
was treated three times with 10 ml each time of ethanol. The
combined alcoholic phases were concentrated under reduced pressure
and codistilled twice more with toluene. The residue thus obtained
(1.58 g of 8-azaspiro[4.5]decane-8-sulfonic acid sodium salt) was
suspended in 30 ml of toluene and admixed under argon with 1.65 g
of phosphorus pentachloride (1.1 eq.) The reaction mixture thus
obtained was stirred at 100.degree. C. for 18 h. After cooling, the
reaction mixture was filtered off from undissolved constituents and
the filtrate was concentrated under reduced pressure. In this way,
8-azaspiro[4.5]decane-8-sulfonyl chloride was obtained as a
colorless oil which was used in the next reaction without further
purification.
[0410] Yield: 520 mg (30% of theory).
Example 72
Methyl
(S)-2-(8-azaspiro[4.5]decane-8-sulfonylamino)-4,4-difluoro-pentanoa-
te
##STR00084##
[0412] In a reaction vessel, 100 mg of methyl
(S)-2-amino-4,4-difluoropentanoate hydrochloride (0.49 mmol) were
admixed with 320 mg of N,O-bis(trimethylsilyl)-acetamide (3.2 eq.)
in 3 ml of acetonitrile. The reaction mixture was treated at
100.degree. C. in a microwave for 30 min. 128 mg of
8-azaspiro[4.5]decane-8-sulfonyl chloride (1.1 eq.), dissolved in
2.5 ml of acetonitrile, were then added and the resulting reaction
mixture was treated at 100.degree. C. in a microwave for a further
2.5 h. The reaction mixture was concentrated under reduced pressure
and the resulting residue was purified by preparative HPLC
(gradient: acetonitrile/water and addition of 0.05% TFA). Methyl
(S)-2-(8-azaspiro[4.5]decane-8-sulfonylamino)-4,4-difluoropentanoate
was obtained as a colorless amorphous material.
[0413] Yield: 75 mg, (41% of theory) MS (ESI.sup.+): 369.
Example 73
(S)-2-(8-Azaspiro[4.5]decane-8-sulfonylamino)-4,4-difluoropentanoic
acid
##STR00085##
[0415]
(S)-2-(8-Azaspiro[4.5]decane-8-sulfonylamino)-4,4-difluoropentanoic
acid was prepared analogously to example 62 starting from 50 mg of
methyl
(S)-2-(8-azaspiro[4.5]decane-8-sulfonylamino)-4,4-difluoropentanoate
(0.14 mmol).
[0416] Yield: 30 mg (62% of theory)
Example 74
N-(1-Cyanocyclopropyl)-(S)-2-(8-azaspiro[4.5]decane-8-sulfonylamino)-4,4-d-
ifluoropentamide
##STR00086##
[0418] 12.0 mg of 1-aminocyclopropanecarbonitrile hydrochloride
(1.2 eq.), 13.8 mg of HOAt (1.2 eq.), 33 .mu.l of N-ethylmorpholine
(3 eq.) and 19.5 mg of EDCI (1.2 eq.) were added successively to a
solution of 30.0 mg of
(S)-2-(8-azaspiro[4.5]decane-8-sulfonylamino)-4,4-difluoropentanoic
acid (0.08 mmol) in 2 ml of THF and 1 ml of dichloromethane. The
reaction mixture was stirred at RT for 4 h and then concentrated
under reduced pressure. The residue thus obtained was purified by
preparative HPLC (gradient: acetonitrile/water and addition of
0.05% TFA). The product-containing fractions were combined and
freeze-dried. In this way,
N-(1-cyanocyclopropyl)-(S)-2-(8-azaspiro[4.5]decane-8-sulfonylamino)-4,4--
difluoropentamide was obtained as a colorless amorphous
material.
[0419] Yield: 20 mg, 56% of theory.
[0420] .sup.1H NMR: 9.1 (5, 1H); 7.85 (d, 1H); 3.85 (m, 1H); 3.00
(m, 4H); 2.15 (m, 2H); 1.65 (t, 3H); 1.55 (m, 4H), 1.50 (m, 2H);
1.40 (t, 4H); 1.37 (m, 4H); 1.10 (m, 2H);
[0421] MS (ESI.sup.+): 419.1.
[0422] Analogously to the examples described in detail above
(examples 1-35 and 58-74), the following further compounds were
prepared.
[0423] These further compounds are shown in table 1b) with
accompanying characterization:
TABLE-US-00002 TABLE 1b Molar Ex- mass am- (parent MS ple compound)
Structure (ESI.sup.+) .sup.1H NMR 75 325.36 ##STR00087## 326.2 9.03
(s, 1H); 8.35 (d, 1H); 4.49 (m, 1H); 1.85-2.40 (m, 9H); 1.62 (t,
3H); 1.50 (d, 2H); 1.10 (d, 2H); 0.75-0.95 (m, 2H) 76 412.48
##STR00088## 413.1 8.85 (s, 1H); 6.70 (d, 1H); 4.30 (m, 1H);
3.20-3.40 (m, 4H); 2.25 (m, 2H); 1.80 (m, 4H); 1.62 (t, 3H); 1.45
(m, 6H); 1.20 (s, 6H); 1.10 (m, 2H) 77 382.46 ##STR00089## 383.1
8.87 (s, 1H); 6.28 (d, 1H); 4.30 (m, 1H); 3.22-3.38 (m, 2H); 3.08
(m, 2H); 2.20- 2.38 (m, 2H); 1.55- 1.68 (m, 5H); 1.30- 1.52 (m, 12
H); 1.10 (d, 2H) 78 432.47 ##STR00090## 433.3 8.90 (s, 1H); 7.29
(m, 3H); 7.20 (m, 1H); 6.80 (d, 1H); 5.00 (s, 2H); 4.35 (m, 1H);
4.00 (m, 2H); 3.05 (m, 2H); 2.30 (m, 2H); 1.80 (m, 2H); 1.65 (t,
3H); 1.58 (m, 2H); 1.50 (d, 2H); 1.10 (d, 2H) 79 430.50
##STR00091## 431.1 8.90 (s, 1H); 7.31 (m, 1H); 7.05-7.20 (m, 3H);
6.40 (d, 1H); 4.38 (m, 1H); 3.30-3.45 (m, 4H); 2.80 (t, 2H); 2.15-
2.40 (m, 4H); 1.90 (m, 1H); 1.60-1.80 (m, 6H); 1.50 (d, 2H); 1.10
(d, 2H) 80 384.43 ##STR00092## 385.3 8.85 (s, 1 H); 6.35 (d, 1H);
4.30 (m, 1H); 3.90 (t, 2H); 3.50 (q, 2H); 3.30- 3.40 (m, 2H); 2.20-
2.40 (m, 4H); 1.38- 1.65 (m, 11H); 1.10 (d, 2H) 81 400.43
##STR00093## 401.2 9.05 (s, 1H); 6.69 (d, 1H); 6.60 (d, 1H); 4.32
(m, 1H), 3.86 (s, 4H); 3.48 (m, 1H); 2.05-2.32 (m, 2H); 1.72 (m,
2H); 1.58-1.68 (m, 5H); 1.45-1.55 (m, 4H); 1.38 (m, 2H); 1.10 (dd,
2H) 82 444.53 ##STR00094## 445.4 8.81 (s, 1H); 7.50 (t, 1H);
7.05-7.29 (m, 3H); 6.60 (t, 1H); 4.35 (m, 1 H); 3.90-4.10 (m, 2H);
2.72-2.90 (m, 2H); 2.70 (s, 2H); 2.19- 2.35 (m, 2H); 1.85- 2.05 (m,
2H); 1.39- 1.75 (m, 11H); 1.10 (d, 2H) 83 409.48 ##STR00095## 410.3
Fumarate: 8.90 (s, 1H); 6.60 (s, 2H); 6.50 (d, 1H); 4.25 (m, 1H);
3.58 (d, 2H); 3.48 (d, 2H); 2.25-2.55 (m, 6H); 2.15 (m, 1H); 1.50-
1.68 (m, 7 H); 1.45 (d, 2H); 1.10 (d, 2H); 0.40 (d, 2H); 0.28 (d,
2H) 84 409.48 ##STR00096## 410.3 Fumarate: 8.85 (s, 1H); 6.68 (d,
1H); 6.60 (s, 2H); 4.30 (m, 1H); 3.15-3.50 (m, 4H); 3.05 (s, 4H);
2.25 (m, 2H); 1.95 (m, 1H); 1.52- 1.65 (m, 7H); 1.48 (m, 2H); 1.10
(m, 2H); 0.34 (d, 2H); 0.25 (d, 2H) 85 411.50 ##STR00097## 412.4
Fumarate: 8.90 (s, 1H); 6.72 (d, 1H), 6.50 (s, 2H); 4.28 (m, 1H);
3.10-3.50 (m, 8H); 2.65 (m, 2H); 2.25 (m, 2H); 1.53-1.65 (m, 7H);
1.45 (d, 2H); 1.38 (q, 2H); 1.10 (m, 2H); 0.87 (t, 3H) 86 439.51
##STR00098## 440.3 TFA salt: 9.02 (s.sub.b, 1H); 8.88 (s, 1H); 6.75
(d, 1H); 4.30 (m, 1H); 3.40-3.90 (m, 6H); 2.88-3.25 (m, 6H);
2.15-2.35 (m, 3H); 1.62 (t, 3H); 1.35-1.48 (m, 4H); 1.10 (d, 2H);
0.90-1.05 (m, 2H); 0.78 (m, 2H) 87 439.51 ##STR00099## 440.3 TFA
salt: 8.90 (s, 1H); 8.70 (s.sub.b, 1H); 6.82 (d, 1H); 4.32 (m, 1H);
3.35-3.70 (m, 8H); 3.15-3.33 (m, 4H); 2.95 (m, 1H); 2.25 (m, 2H);
2.03 (t, 2H); 1.62 (t, 3H); 1.50 (d, 2H); 1.10 (d, 2H); 0.90 (d,
2H); 0.80 (d, 2H) 88 451.52 ##STR00100## 452.3 8.85 (s, 1H); 6.72
(d, 1 H); 4.30 (m, 1H); 3.40 (m, 4H); 3.25 (m, 4H); 3.05 (d, 2H);
2.25 (m, 2H); 2.15 (s, 2H); 1.62 (t, 3 H); 1.45 (m, 5H); 1.10 (m,
2H); 0.45 (d, 2H); 0.20 (d, 2H) 89 444.53 ##STR00101## 445.1 8.45
(s, 1H); 7.10- 7.28 (m, 4H); 5.90 (d, 1H); 4.38 (m, 1H); 3.30-3.60
(m, 4H); 2.90 (t, 2H); 2.15-2.40 (m, 2H); 1.75-2.10 (m, 6H);
1.38-1.52 (m, 4H); 1.15 (m, 2H); 0.90 (t, 3H) 90 531.61
##STR00102## 532.2 8.88 (s, 1H); 7.58 (d, 2H); 6.95 (d, 2H); 6.77
(d, 1H); 4.30 (m, 1H); 3.90 (m, 2H); 3.77 (m, 2H); 3.73 (s, 3H);
2.90 (m, 2H); 2.25 (m, 2H); 2.10 (t, 2H); 1.85 (m, 2H); 1.65 (q,
2H); 1.40- 1.50 (m, 6H); 1.10 (m, 2H); 0.90 (t, 3H) 91 517.62
##STR00103## 518.2 8.85 (s, 1H); 6.82 (d, 2H); 6.70 (d, 1H); 6.55
(d, 2H), 4.30 (m, 1H); 3.68 (s, 3H); 3.25-3.55 (m, 6H); 3.10 (s,
2H); 2.25 (m, 2H); 1.80 (m, 4H); 1.35-1.55 (m, 8H), 1.10 (d, 2H);
0.90 (t, 3H) 92 437.54 ##STR00104## 436.3 (ES.sup.-) TFA salt: 9.80
(s.sub.b, 1H); 8.90 (s, 1H); 6.75 (d, 1H); 4.30 (m, 1H); 3.97 (m,
2H); 3.90 (m, 2H); 3.15-3.30 (m, 4H); 3.10 (m, 1H); 2.15- 2.30 (m,
2H); 1.75- 1.86 (m, 2H); 1.70 (s, 4H); 1.45 (d, 2H); 1.40 (m, 2H);
1.10 (d, 2H); 0.89 (t, 3H); 0.80 (d, 4H) 93 451.56 ##STR00105##
452.3 TFA salt: 9.45 (s.sub.b, 1H); 8.90 (s, 1H); 6.72 (d, 1H);
4.31 (m, 1H); 3.52-3.70 (m, 2H); 3.20-3.40 (m, 4H); 3.05 (m, 1H);
2.95 (m, 1H); 2.25 (m, 2H); 2.00 (m, 1H); 1.72-1.88 (m, 4H); 1.58
(m, 1H); 1.38-1.55 (m, 7H); 1.10 (d, 2H); 0.90 (m, 5H); 0.82 (d,
2H) 94 465.59 ##STR00106## 464.3 (ES.sup.-) TFA salt: 8.89 (s, 1H);
8.52 (s.sub.b, 1H); 6.70 (d, 1H); 4.30 (m, 1H); 3.20-3.40 (m, 8H);
2.90 (m, 1H); 2.20-2.30 (m, 2H); 1.78-1.88 (m, 4H); 1.57 (s.sub.b,
2H); 1.35-1.49 (m, 6H); 1.29 (s.sub.b, 2H); 1.10 (d, 2 H); 0.90 (m,
5H); 0.82 (d, 2H) 95 437.54 ##STR00107## 438.2 TFA salt: 8.90 (s,
1H); 8.68 (s.sub.b, 1H); 6.65 (d, 1H); 4.29 (m, 1H); 3.70 (d, 1H);
3.65 (dd, 2H); 3.55 (d, 1H); 3.30- 3.45 (m, 2H); 3.12 (m, 2H); 2.87
(s.sub.b, 1H); 2.12-2.40 (m, 2H); 2.05 (m, 2H); 1.73-1.89 (m, 4H);
1.50 (d, 2H); 1.40 (m, 2H); 1.10 (dd, 2H); 0.90 (m, 5H); 0.85 (d,
2H) 96 439.55 ##STR00108## 438.3 (ES.sup.-) TFA salt: 9.01
(s.sub.b, 1H); 8.90 (s, 1H); 6.62 (d, 1H); 4.29 (m, 1H); 3.50-3.68
(m, 4H); 3.25-3.40 (m, 2H); 3.00 (m, 2H); 2.87 (q, 2H); 2.10-2.38
(m, 2H); 2.02 (m, 2H); 1.80 (m, 4H); 1.65 (m, 2H); 1.50 (d, 2H);
1.40 (m, 2H); 1.10 (d, 2H); 0.90 (t, 6H) 97 513.64 ##STR00109##
514.2 TFA salt: 8.89 (s, 1H); 8.51 (s.sub.b, 1H); 7.22-7.39 (m,
5H); 6.72 (d, 1H); 4.39 (m, 1H); 3.20-3.40 (m, 10H); 2.90 (m, 1H);
2.35 (m, 1H); 2.18 (m, 1H); 1.80-1.90 (m, 2H); 1.57 (s.sub.b, 2H);
1.38- 1.48 (m, 4H); 1.28 (t, 2 H); 1.10 (dd, 2H); 0.90 (d, 2H);
0.80 (d, 2H) 98 485.58 ##STR00110## 486.2 TFA salt: 9.80 (s.sub.b,
1H); 8.90 (s, 1H); 7.23-7.40 (m, 5H); 6.75 (d, 1H); 4.38 (m, 1 H);
3.95 (m, 2H); 3.89 (m, 2H); 3.15-3.42 (m, 6H); 3.09 (m, 1H); 2.38
(m, 1H); 2.20 (m, 1H); 1.59-1.69 (m, 4H); 1.50 (d, 2H); 1.10 (dd,
2H); 0.80 (d, 4H) 99 487.60 ##STR00111## 488.2 TFA salt: 9.80
(s.sub.b, 1H); 8.90 (s, 1H); 7.23-7.42 (m, 5H); 6.75 (d, 1H); 4.38
(m, 1 H); 3.92 (m, 2H); 3.82 (m, 2H); 3.15-3.40 (m, 6H); 3.11 (t,
2H); 2.35 (m, 1H); 2.15 (m, 1H); 1.60-1.75 (m, 4H); 1.39-1.46 (m,
4H); 1.10 (dd, 2H); 0.90 (t, 3H) 100 485.58 ##STR00112## 486.2 TFA
salt: 8.90 (s, 1H); 8.60 (d.sub.b, 1H); 7.20-7.40 (m, 5H); 6.60 (d,
1H); 4.40 (m, 1H); 3.40-3.70 (m, 6H); 3.25 (t, 2H); 3.10 (q, 2H);
2.85 (m, 1H); 2.35 (m, 1H), 2.15 (m, 1H); 2.0 (m, 2H); 1.72 (t,
2H); 1.50 (d, 2H); 1.10 (dd, 2H); 0.90 (d, 2H); 0.80 (d, 2H) 101
328.36 ##STR00113## 329.2 8.58 (t, 1H); 6.75 (d, 1H); 4.40 (m, 1H);
4.10 (d, 2 H); 3.30-3.40 (m, 4H); 2.25 (m, 2H); 1.62 (t, 3H); 1.25
(m, 4H); 0.30 (s, 4 H) 102 382.46 ##STR00114## 383.3 8.85 (s, 1H);
6.70 (d, 1H); 4.30 (m, 1H); 3.30-3.40 (m, 4H); 2.25 (m, 2H); 1.82
(m, 2H); 1.48 (d, 2H); 1.42 (m, 2H); 1.25 (m, 4H), 1.10 (m, 2H),
0.90 (t, 3H). 0.30 (s, 4 H) 103 411.50 ##STR00115## 412.2 8.41 (s,
1H); 6.70 (d, 2H); 4.42 (m, 1H); 3.30-3.40 (m, 4H); 2.55 (m, 2H);
2.10-2.40 (m, 9H); 1.88 (m, 2H); 1.25 (m, 6H); 0.30 (s, 4H) 104
439.55 ##STR00116## 440.5 8.40 (s, 1H); 6.70 (d, 1H); 4.40 (q, 1H);
4.05 (m, 2H); 3.40 (m, 4H); 2.18-2.35 (m, 4H); 2.15 (s, 3H);
1.78-1.94 (m, 4H); 1.42 (m, 2H); 1.26 (t, 4H); 1.19 (m, 2H); 0.90
(t, 3H); 0.30 (s, 4H) 105 368.43 ##STR00117## 369.4 8.82 (s, 1H);
6.68 (d, 1H); 4.30 (m, 1H); 3.29-3.40 (m, 4H); 2.30 (m, 2H); 1.88
(m, 2H); 1.48 (m, 2H); 1.25 (t, 4H); 1.10 (m, 2H); 0.90 (t, 3H);
0.30 (s, 4H)
[0424] The examples which follow can be prepared in an analogous
manner: [0425]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-5-methylhexyl-
]-6-azaspiro[2.5]octane-6-carboxamide
[0425] ##STR00118## [0426]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-4-cyclopropyl-3,3-difluorobutyl]--
6-azaspiro[2.5]octane-6-carboxamide
[0426] ##STR00119## [0427]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-(2-methoxyphenyl)b-
utyl]-6-azaspiro[2.5]octane-6-carboxamide
[0427] ##STR00120## [0428]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-(2-trifluoromethox-
yphenyl)-butyl]-6-azaspiro[2.5]octane-6-carboxamide
[0428] ##STR00121## [0429]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-(2-fluorophenyl)bu-
tyl]-6-azaspiro[2.5]octane-6-carboxamide
[0429] ##STR00122## [0430]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-(4-fluorophenyl)bu-
tyl]6-azaspiro[2.5]octane-6-carboxamide
[0430] ##STR00123## [0431]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-pyridin-2-ylbutyl]-
-6-aza-spiro[2.5]octane-6-carboxamide
[0431] ##STR00124## [0432]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-pyridin-3-ylbutyl]-
-6-aza-spiro[2.5]octane-6-carboxamide
[0432] ##STR00125## [0433]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-pyridin-4-ylbutyl]-
-6-aza-spiro[2.5]octane-6-carboxamide
[0433] ##STR00126## [0434]
N--[(S)-1-(cyanomethylcarbamoyl)-3,3-difluoro-4-phenylbutyl]-6-azaspiro[2-
.5]octane-6-carboxamide
[0434] ##STR00127## [0435]
N--[(S)-1-(cyanomethylcarbamoyl)-4-cyclopropyl-3,3-difluorobutyl]-6-aza-s-
piro[2.5]octane-6-carboxamide
[0435] ##STR00128## [0436]
N--[(S)-1-(cyanomethylcarbamoyl)-3,3-difluoro-4-pyridin-3-ylbutyl]-6-aza--
spiro[2.5]octane-6-carboxamide
[0436] ##STR00129## [0437]
N--[(S)-1-(cyanomethylcarbamoyl)-4-(2-difluoromethoxyphenyl)-3,3-difluoro-
butyl]-6-azaspiro[2.5]octane-6-carboxamide
[0437] ##STR00130## [0438]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-7-azaspiro[3.5-
]nonane-7-carboxamide
[0438] ##STR00131## [0439]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-4-cyclopropyl-3,3-difluorobutyl]--
7-aza-spiro[3.5]nonane-7-carboxamide
[0439] ##STR00132## [0440]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-phenylbutyl]-7-aza-
-spiro[3.5]nonane-7-carboxamide
[0440] ##STR00133## [0441]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-pyridin-2-ylbutyl]-
-7-aza-spiro[3.5]nonane-7-carboxamide
[0441] ##STR00134## [0442]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-pyridin-3-ylbutyl]-
-7-aza-spiro[3.5]nonane-7-carboxamide
[0442] ##STR00135## [0443]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-pyridin-4-ylbutyl]-
-7-aza-spiro[3.5]nonane-7-carboxamide
[0443] ##STR00136## [0444]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-(2-methoxyphenyl)b-
utyl]-7-cyclopropyl-2,7-diazaspiro[3.5]nonane-2-carboxamide
[0444] ##STR00137## [0445]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-(2-fluorophenyl)bu-
tyl]-7-cyclopropyl-2,7-diazaspiro[3.5]nonane-2-carboxamide
[0445] ##STR00138## [0446]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-(4-fluorophenyl)bu-
tyl]-7-cyclopropyl-2,7-diazaspiro[3.5]nonane-2-carboxamide
[0446] ##STR00139## [0447]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-pyridin-2-ylbutyl]-
-7-cyclopropyl-2,7-diazaspiro[3.5]nonane-2-carboxamide
[0447] ##STR00140## [0448]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-pyridin-3-ylbutyl]-
-7-cyclopropyl-2,7-diazaspiro[3.5]nonane-2-carboxamide
[0448] ##STR00141## [0449]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-pyridin-4-ylbutyl]-
-7-cyclopropyl-2,7-diazaspiro[3.5]nonane-2-carboxamide
[0449] ##STR00142## [0450]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-5-methylhexyl]-7-cyc-
lopropyl-2,7-diazaspiro[3.5]nonane-2-carboxamide
[0450] ##STR00143## [0451]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-4-cyclopropyl-3,3-difluorobutyl]--
7-cyclopropyl-2,7-diazaspiro[3.5]nonane-2-carboxamide
[0451] ##STR00144## [0452]
N--[(S)-1-(cyanomethylcarbamoyl)-3,3-difluoro-4-phenylbutyl]-7-cyclopropy-
l-2,7-di-azaspiro[3.5]nonane-2-carboxamide
[0452] ##STR00145## [0453]
N--[(S)-1-(cyanomethylcarbamoyl)-3,3-difluoro-4-pyridin-3-ylbutyl]-7-cycl-
opropyl-2,7-diazaspiro[3.5]nonane-2-carboxamide
[0453] ##STR00146## [0454]
N--[(S)-1-(cyanomethylcarbamoyl)-4-cyclopropyl-3,3-difluorobutyl]-7-cyclo-
propyl-2,7-diazaspiro[3.5]nonane-2-carboxamide
[0454] ##STR00147## [0455]
N--[(S)-1-(cyanomethylcarbamoyl)-3,3-difluoro-4-(2-fluorophenyl)butyl]-7--
cyclopropyl-2,7-diazaspiro[3.5]nonane-2-carboxamide
[0455] ##STR00148## [0456]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-1,1-difluoro-6-
-aza-spiro[2.5]octane-6-carboxamide
[0456] ##STR00149## [0457]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoropentyl]-1,1-difluoro--
6-aza-spiro[2.5]octane-6-carboxamide
[0457] ##STR00150## [0458]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-4-cyclopropyl-3,3-difluorobutyl]--
1,1-difluoro-6-azaspiro[2.5]octane-6-carboxamide
[0458] ##STR00151## [0459]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-pyridin-3-ylbutyl]-
-1,1-difluoro-6-azaspiro[2.5]octane-6-carboxamide
[0459] ##STR00152## [0460]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-4,4-difluoropentyl]-6-azaspiro[2.-
5]octane-6-carboxamide
[0460] ##STR00153## [0461]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-4,4-difluoro-4-phenylbutyl]-6-aza-
-spiro[2.5]octane-6-carboxamide
[0461] ##STR00154## [0462]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-4,4-difluoro-4-pyridin-2-ylbutyl]-
-6-aza-spiro[2.5]octane-6-carboxamide
[0462] ##STR00155## [0463]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-4,4-difluoro-4-pyridin-3-ylbutyl]-
-6-aza-spiro[2.5]octane-6-carbonsaure
[0463] ##STR00156## [0464]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-4,4-difluoro-4-pyridin-4-ylbutyl]-
-6-aza-spiro[2.5]octane-6-carboxamide
[0464] ##STR00157## [0465]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-4-(2-difluoromethoxyphenyl)-4,4-d-
ifluoro-butyl]-6-azaspiro[2.5]octane-6-carboxamide
[0465] ##STR00158## [0466]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-4,4-difluoro-4-(4-fluorophenyl)bu-
tyl]-6-aza-spiro[2.5]octane-6-carboxamide
[0466] ##STR00159## [0467]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-4,4-difluoro-4-(2-fluorophenyl)bu-
tyl]-6-aza-spiro[2.5]octane-6-carboxamide
[0467] ##STR00160## [0468]
N--[(S)-1-(4-cyano-1-methylpiperidin-4-ylcarbamoyl)-4,4-difluoro-4-phenyl-
butyl]-6-aza-spiro[2.5]octane-6-carboxamide
[0468] ##STR00161## [0469]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-4,4-difluoro-4-phenylbutyl]-7-cyc-
lopropyl-2,7-diazaspiro[3.5]nonane-2-carboxamide
[0469] ##STR00162## [0470]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-4,4-difluoro-4-(4-fluorophenyl)bu-
tyl]-7-cyclopropyl-2,7-diazaspiro[3.5]nonane-2-carboxamide
[0470] ##STR00163## [0471]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-4,4-difluoro-4-(2-fluorophenyl)bu-
tyl]-7-cyclopropyl-2,7-diazaspiro[3.5]nonane-2-carboxamide
[0471] ##STR00164## [0472]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-4-(2-difluoromethoxyphenyl)-4,4-d-
ifluorobutyl]-7-cyclopropyl-2,7-diazaspiro[3.5]nonane-2-carboxamide
[0472] ##STR00165## [0473]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-4,4-difluoro-4-pyridin-2-ylbutyl]-
-7-cyclopropyl-2,7-diazaspiro[3.5]nonane-2-carboxamide
[0473] ##STR00166## [0474]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-4,4-difluoro-4-pyridin-3-ylbutyl]-
-7-cyclopropyl-2,7-diazaspiro[3.5]nonane-2-carboxamide
[0474] ##STR00167## [0475]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-4,4-difluoro-4-pyridin-4-ylbutyl]-
-7-cyclopropyl-2,7-diazaspiro[3.5]nonane-2-carboxamide
[0475] ##STR00168## [0476]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-phenylbutyl]-7-met-
hyl-2,7-diazaspiro[3.5]nonane-2-carboxamide
[0476] ##STR00169## [0477]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-phenylbutyl]-7-(2--
methoxyethyl)-2,7-diazaspiro[3.5]nonane-2-carboxamide
[0477] ##STR00170## [0478]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-phenylbutyl]-9-(2--
methoxyethyl)-3,9-diazaspiro[5.5]undecane-3-carboxamide
[0478] ##STR00171## [0479]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-phenylbutyl]-7-ami-
no-5-aza-spiro[2.4]heptane-5-carboxamide
[0479] ##STR00172## [0480]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-phenylbutyl]-7-dim-
ethylamino-5-azaspiro[2.4]heptane-5-carboxamide
[0480] ##STR00173## [0481]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-7-(cyclopropan-
ecarbonyl-amino)-5-azaspiro[2.4]heptane-5-carboxamide
[0481] ##STR00174## [0482]
N-6-[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutylcarbamoyl]-6-az-
a-spiro[2.5]octane-1-carboxylic acid
[0482] ##STR00175## [0483] ethyl
6-[(S)-1-(1-canocyclopropylcarbamoyl)-3,3-difluorobutylcarbamoyl]-6-azasp-
iro[2.5]octane-1-carboxylate
[0483] ##STR00176## [0484]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-1-hydroxymethy-
l-6-aza-spiro[2.5]octane-6-carboxamide
[0484] ##STR00177## [0485]
8-[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutylcarbamoyl]-1-oxa--
2,8-diaza-spiro[4.5]dec-2-ene-3-carboxylic acid
[0485] ##STR00178## [0486]
8-[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-phenylbutylcarbamoy-
l]-1-oxa-2,8-diazaspiro[4.5]dec-2-ene-3-carboxylic acid
[0486] ##STR00179## [0487]
8-[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoropentylcarbamoyl]-1-oxa-
-2,8-diaza-spiro[4.5]dec-2-ene-3-carboxylic acid
[0487] ##STR00180## [0488]
7-[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-phenylbutylcarbamoy-
l]-1-oxa-2,7-diazaspiro[4.5]dec-2-ene-3-carboxylic acid
[0488] ##STR00181## [0489]
7-[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-phenylbutylcarbamoy-
l]-1-oxa-2,7-diazaspiro[4.4]non-2-ene-3-carboxylic acid
[0489] ##STR00182## [0490]
{3-[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutylcarbamoyl]-3-aza-
-spiro[5.5]undec-9-yl}acetic acid
[0490] ##STR00183## [0491]
{3-[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoropentylcarbamoyl]-3-az-
a-spiro[5.5]undec-9-yl}acetic acid
[0491] ##STR00184## [0492]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoropentyl]-1,3-dioxo-2,8-
-diazaspiro[4.5]decane-8-carboxamide
[0492] ##STR00185## [0493]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-1,3-dioxo-2,8--
diaza-spiro[4.5]decane-8-carboxamide
[0493] ##STR00186## [0494]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-phenylbutyl]-1,3-d-
ioxo-2,8-diazaspiro[4.5]decane-8-carboxamide
[0494] ##STR00187## [0495]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-5-methylhexyl]-5-aza-
-spiro[2.5]octane-5-carboxamide
[0495] ##STR00188## [0496]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-5-azaspiro[2.5-
]octane-5-carboxamide
[0496] ##STR00189## [0497]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-phenylbutyl]-5-aza-
-spiro[2.5]octane-5-carboxamide
[0497] ##STR00190## [0498]
N--[(S)-1-(cyanomethylcarbamoyl)-3,3-difluorobutyl]-5-azaspiro[2.5]octane-
-5-carboxamide
[0498] ##STR00191## [0499]
N--[(S)-1-(cyanomethylcarbamoyl)-3,3-difluoro-4-phenylbutyl]-5-azaspiro[2-
.5]octane-5-carboxamide
[0499] ##STR00192## [0500]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-(4-fluorophenyl)-b-
utyl]-5-azaspiro[2.5]octane-5-carboxamide
[0500] ##STR00193## [0501]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-8-cyclopropyl--
1-oxa-2,8-diazaspiro[4.5]dec-2-ene-3-carboxamide
[0501] ##STR00194## [0502]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-8-propyl-1-oxa-
-2,8-diaza-spiro[4.5]dec-2-en-3-carboxamide
[0502] ##STR00195## [0503]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-7-cyclopropyl--
1-oxa-2,7-diazaspiro[4.5]dec-2-ene-3-carboxamide
[0503] ##STR00196## [0504]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-7-propyl-1-oxa-
-2,7-diaza-spiro[4.5]dec-2-ene-3-carboxamide
[0504] ##STR00197## [0505]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-7-cyclopropyl--
1-oxa-2,7-diazaspiro[4.4]non-2-ene-3-carboxamide
[0505] ##STR00198## [0506]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-7-methyl-1-oxa-
-2,7-diaza-spiro[4.4]non-2-ene-3-carboxamide
[0506] ##STR00199## [0507]
N--[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-phenylbutyl]-7-met-
hyl-1-oxa-2,7-diazaspiro[4.4]non-2-ene-3-carboxamide
##STR00200##
[0507] Pharmacological Examples
[0508] Determination of the enzymatic activity of the catalytic
domain of human Cathepsin B. This protein is obtained as an
inactive enzyme from Sigma, Wiesbaden, Germany (catalog No. C8571).
The enzyme is activated as follows:
25 .mu.g of enzyme are diluted with acetate buffer to a
concentration of 12.5 .mu.g/ml. 1 part by volume of enzyme is
admixed with 20 parts by volume of cysteine solution and diluted
with the acetate/Hepes buffer to a concentration of 0.11 .mu.g/ml
and incubated at 37.degree. C. for 5 minutes.
[0509] To measure the enzyme activity, 10 .mu.l of enzyme solution
are incubated with 10 .mu.l of a 3% (v/v) aqueous dimethyl
sulfoxide solution (reaction 1) for 10 minutes. To measure the
enzyme inhibitor activity, 10 .mu.l of enzyme solution are
incubated with 10 .mu.l of a 3% (v/v) aqueous dimethyl sulfoxide
solution which contains the enzyme inhibitor (reaction 2).
[0510] Both in reaction 1 and in reaction 2, after addition of 10
.mu.l of a 3% (v/v) aqueous dimethyl sulfoxide solution which
contains 0.3 mmol/l of the substrate, the enzyme reaction is
monitored by fluorescence spectroscopy (360 nm (excitation)/465 nm
(emission)).
[0511] The enzyme activity is shown as fluorescence
increase/minute.
[0512] The inhibitor action is calculated as the percentage
inhibition by the following formula:
% inhibition=100-[(fluorescence increase/minute in reaction
2)/(fluorescence increase/minute in reaction 1).times.100].
[0513] The IC.sub.50, which is the inhibitor concentration required
for a 50% inhibition in the enzyme activity, is determined
graphically by plotting the percentage inhibitions at different
inhibitor concentrations.
[0514] The acetate buffer contains 0.1 mol/l of sodium acetate, 0.1
mol/l of sodium chloride and 0.001% Pluronic (Sigma, Deisenhofen,
Germany) pH 4.5.
[0515] The cysteine solution contains 0.3 mol/l of cysteine in
water. The acetate/Hepes buffer contains 0.15 mol/l of sodium
acetate, 0.15 mol/l of Hepes, 0.3 mol/l of sodium chloride and
0.001% Pluronic (Sigma, Deisenhofen, Germany) pH 6.5.
[0516] The enzyme solution contains 0.11 .mu.g/ml of the enzyme
domain.
[0517] The substrate solution contains 0.3 mmol/l of the
fluorogenic substrate 2-Arg-Arg-AMC (Bachem, Heidelberg,
Germany).
[0518] Determination of the enzymatic activity of the catalytic
domain of human Cathepsin K.
[0519] This protein is obtained as an inactive enzyme from
Sanofi-Aventis, Frankfurt, Germany. The enzyme is activated as
follows: 1 part by volume of enzyme is admixed with 4 parts by
volume of cysteine solution and diluted with the acetate/Hepes
buffer to a concentration of 0.22 .mu.g/ml.
[0520] To measure the enzyme activity, 10 .mu.l of enzyme solution
are incubated with 10 .mu.l of a 3% (v/v) aqueous dimethyl
sulfoxide solution (reaction 1) for 10 minutes. To measure the
enzyme inhibitor activity, 10 .mu.l of enzyme solution are
incubated with 10 .mu.l of a 3% (v/v) aqueous dimethyl sulfoxide
solution which contains the enzyme inhibitor (reaction 2).
[0521] Both in reaction 1 and in reaction 2, after addition of 10
.mu.l of a 3% (v/v) aqueous dimethyl sulfoxide solution which
contains 0.3 mmol/l of the substrate, the enzyme reaction is
monitored by fluorescence spectroscopy (360 nm (excitation)/465 nm
(emission)).
[0522] The enzyme activity is shown as fluorescence
increase/minute.
[0523] The inhibitor action is calculated as the percentage
inhibition by the following formula:
% inhibition=100-[(fluorescence increase/minute in reaction
2)/(fluorescence increase/minute in reaction 1).times.100].
[0524] The IC.sub.50, which is the inhibitor concentration required
for a 50% inhibition in the enzyme activity, is determined
graphically by plotting the percentage inhibitions at different
inhibitor concentrations.
[0525] The cysteine solution contains 0.3 mol/l of cysteine in
water. The acetate/Hepes buffer contains 0.15 mol/l of sodium
acetate, 0.15 mol/l of Hepes, 0.3 mol/l of sodium chloride and
0.001% Pluronic (Sigma, Deisenhofen, Germany) pH 6.5.
[0526] The enzyme solution contains 0.22 .mu.g/ml of the enzyme
domain.
[0527] The substrate solution contains 0.3 mmol/l of the
fluorogenic substrate Boc-Ala-Gly-Pro-Arg-AMC (Bachem, Heidelberg,
Germany).
[0528] Determination of the enzymatic activity of the catalytic
domain of human Cathepsin S.
[0529] This protein is obtained as an inactive enzyme from R&D
Systems, Wiesbaden, Germany (catalog No. 1183-CY). The enzyme is
activated as follows:
5 parts by volume of enzyme are incubated with 20 parts by volume
of acetate buffer and 50 parts by volume of cysteine solution at
37.degree. C. for 5 minutes. After the activation of the enzyme, it
is diluted with the Tris/HCl buffer to a concentration of 0.65
.mu.g/ml. To measure the enzyme activity, 10 .mu.l of enzyme
solution are incubated with 10 .mu.l of a 3% (v/v) aqueous dimethyl
sulfoxide solution (reaction 1) for 10 minutes. To measure the
enzyme inhibitor activity, 10 .mu.l of enzyme solution are
incubated with 10 .mu.l of a 3% (v/v) aqueous dimethyl sulfoxide
solution which contains the enzyme inhibitor (reaction 2). Both in
reaction 1 and in reaction 2, after addition of 10 .mu.l of a 1.5%
(v/v) aqueous dimethyl sulfoxide solution which contains 0.15
mmol/l of the substrate, the enzyme reaction is monitored by
fluorescence spectroscopy (360 nm (excitation)/465 nm
(emission)).
[0530] The enzyme activity is shown as fluorescence
increase/minute.
[0531] The inhibitor action is calculated as the percentage
inhibition by the following formula:
% inhibition=100-[(fluorescence increase/minute in reaction
2)/(fluorescence increase/minute in reaction 1).times.100].
[0532] The IC.sub.50, which is the inhibitor concentration required
for a 50% inhibition in the enzyme activity, is determined
graphically by plotting the percentage inhibitions at different
inhibitor concentrations.
[0533] The acetate buffer contains 0.05 mol/l of sodium acetate,
0.1 mol/l of sodium chloride and 0.001% Pluronic (Sigma,
Deisenhofen, Germany) pH 5.5.
[0534] The cysteine solution contains 0.3 mol/l of cysteine in
water. The Tris/HCl buffer contains 0.1 mol/l of Tris/HCl, 0.04
mol/l of EDTA and 0.001% Pluronic pH=7.5.
[0535] The enzyme solution contains 0.65 .mu.g/ml of the enzyme
domain.
[0536] The substrate solution contains 0.15 mmol/l of the
fluorogenic substrate Z-Val-Val-Arg-AMC (Bachem, Heidelberg,
Germany).
[0537] Corresponding Ki values are obtained by applying the
Cheng-Prusoff equation:
K.sub.i=K.sub.i,app/(1+[S]/K.sub.m);
where K.sub.i, app=IC.sub.50 (K.sub.i, app is the concentration of
the competing substance which leads to 50% inhibition of the
enzymatic activity at a substrate concentration [S])
[0538] Table 2 reports corresponding inhibition values in the form
of Ki values for a few representative examples:
TABLE-US-00003 TABLE 2 Ki [nM] Ki [nM] Ki [nM] Example Cathepsin K
Cathepsin B Cathepsin S 9 1.8 46 3.2 35 31 >7100 150 36 3 44 2
37 21 560 13 42 32 4500 11 45 21 1200 24 49 52 2200 16 53 4.5 1500
53 56 7.5 210 7.2 63 22 260 5 70 910 110 0.3 74 150 >7100 16 76
47 930 22 77 20 220 7 78 38 530 19 79 16 620 9 80 36 3900 9 83 28
2300 8 88 15 310 9 91 43 140 2 94 24 84 2 97 400 100 1 102 33 62
0.5 103 84 99 27
[0539] Caco-2/TC7 permeability determinations for forecasting the
absorption of the inventive compounds: (Caco-2/TC7 permeability
test)
[0540] Caco-2/TC-7 cells from Sanofi are used. In addition, HTS
Multiwell plates (24-well, non-coated, Becton Dickinson, surface
area of the Becton Dickinson Filter 0.3 cm.sup.2) are used. The
cell density on the filters was 2.times.10.sup.5/cm.sup.2, and
1.3.times.10.sup.4/cm.sup.2 on the T-75 flasks (Costar with
vent-cap) for the cell line growth.
[0541] The incubation conditions are 37.degree. C., 95% air
humidity, 10% CO.sub.2. The medium is changed three times per week
(DMEM, Glutamax I, nonessential AA, penicillin/streptomycin, FBS
20%).
[0542] Permeability assay conditions: asymmetric conditions for the
screening with apical buffer HBSS (with 10 mM HEPES and 0.5% BSA at
pH 6.5) and basal buffer HBSS (with 10 .mu.M HEPES and 5% BSA at pH
7.4). The permeability experiments were performed at 37.degree. C.
with agitation for 2 h. The samples were analyzed by LC-MS. The
results were reported as the mean Papp value (single point, cm/sec)
(permeability coefficient):
P = B 2 [ A 0 ] .times. S .times. t ##EQU00001##
B2: basolateral amount of the compound to be analyzed after 2 h
[A.sub.0]: apical concentration of the test solution S: "insert
area": 0.3 cm.sup.2 t: time: 2 h
* * * * *