ZA200408993B - Hydroxy tetrahydro naphthalenylurea derivatives - Google Patents

Hydroxy tetrahydro naphthalenylurea derivatives Download PDF

Info

Publication number
ZA200408993B
ZA200408993B ZA2004/08993A ZA200408993A ZA200408993B ZA 200408993 B ZA200408993 B ZA 200408993B ZA 2004/08993 A ZA2004/08993 A ZA 2004/08993A ZA 200408993 A ZA200408993 A ZA 200408993A ZA 200408993 B ZA200408993 B ZA 200408993B
Authority
ZA
South Africa
Prior art keywords
hydroxy
tetrahydro
naphthalenyl
urea
halogen
Prior art date
Application number
ZA2004/08993A
Inventor
Urbahns Klaus
Yura Takeshi
Kokubo Toshio
Mogi Muneto
Yamamoto Noriyuki
Yoshida Nagahiro
Masuda Tsutomu
Fujishima Hiroshi
Moriwaki Toshiya
Shiroo Masahiro
Tsukimi Yasuhiro
Tajimi Masaomi
Original Assignee
Bayer Healthcare Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/EP2003/004395 external-priority patent/WO2003095420A1/en
Application filed by Bayer Healthcare Ag filed Critical Bayer Healthcare Ag
Publication of ZA200408993B publication Critical patent/ZA200408993B/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/40—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

. ’ : _ 1 - | -
HYDROXY TETRAHYDRO-NAPHTHALENYLUREA DERIVATIVES . DETAILED DESCRIPTION OF INVENTION TECHNICAL FIELD
The present invention relates to hydroxy-tetrahydro-naphthalenylurea derivatives which are useful as an active ingredient of pharmaceutical preparations. The hydroxy-tetrahydro-naphthalenylurea derivatives of the present invention has vanilloid receptor (VR) antagonistic activity, and can be used for the prophylaxis and treatment of diseases associated with VR1 activity, in particular for the treatment of urge urinary incontinence, overactive bladder, chronic pain, neuropathic pain, : postoperative pain, theumatoid arthritic pain, neuralgia, neuropathies, algesia, nerve injury, ischaemia, neurodegeneration, stroke, incontinence and/or inflammatory disorders such as asthma and chronic obstructive pulmonary disease (COPD).
Urinary incontinence (UI) is the involuntary loss of urine. Urge urinary incontinence (UUD) is one of the most common types of UI together with stress urinary incon- tinence (SUI) which is usually caused by a defect in the urethral closure mechanism.
UUT is often associated with neurological disorders or diseases causing neuronal damages such as dementia, Parkinson's disease, multiple sclerosis, stroke and diabetes, although it also occurs in individuals with no such disorders. One of the usual causes of UUI is overactive bladder (OAB) which is a medical condition referring to the symptoms of frequency and urgency derived from abnormal contractions and instability of the detrusor muscle.
There are several medications for urinary incontinence on the market today mainly to help treating UUIL Therapy for OAB is focused on drugs that affect peripheral neural control mechanisms or those that act directly on bladder detrusor smooth muscle contraction, with a major emphasis on development of anticholinergic agents. These
. ~ agents can inhibit the parasympathetic nerves which control bladder voiding or can exert a direct spasmolytic effect on the detrusor muscle of the bladder. This results in a decrease in intravesicular pressure, an increase in capacity and a reduction in the frequency of bladder contraction. Orally active anticholinergic drugs such as \ propantheline (ProBanthine), tolterodine tartrate (Detrol) and oxybutynin (Ditropan) are the most commonly prescribed drugs. However, their most serious drawbacks are unacceptable side effects such as dry mouth, abnormal visions, constipation, and central nervous system disturbances. These side effects lead to poor compliance. Dry mouth symptoms alone are responsible for a 70% non-compliance rate with oxybutynin. The inadequacies of present therapies highlight the need for novel, "efficacious, safe, orally available drugs that have fewer side effects.
BACKGROUND ART | | oo
Vanilloid compounds are characterized by the presence of a vanillyl group or a functionally equivalent group. Examples of several vanilloid compounds or vanilloid receptor modulators are vanillin (4-hydroxy-3-methoxy-benzaldehyde)] guaiacol (2- methoxy-phenol), zingerone (4-/4-hydroxy-3-methoxyphenyl/-2-butanon), eugenol- (2-methoxy4-/2-propenyl/phenol), . and capsaicin (8-methy-N-vanillyl-6-nonene- amide).
Among others, capsaicin, the main pungent ingredient in "hot" chili peppers, is a specific neurotoxin that desensitizes C-fiber afferent neurons. Capsaicin interacts with vanilloid receptors (VR1), which are predominantly expressed in cell bodies of dorsal root ganglia (DRG) or nerve endings of afferent sensory fibers including C- fiber nerve endings [Tominaga M, Caterina MJ, Malmberg AB, Rosen TA, Gilbert
H, Skinner K, Raumann BE, Basbaum Al, Julius D: The cloned capsaicin receptor . integrates multiple pain-producing stimuli. Neuron. 21: 531-543, 1998]. The VR1 receptor was recently cloned [Caterina MJ, Schumacher MA, Tominaga M, Rosen )
TA, Levine JD, Julius D: Nature 389: 816-824, (1997)] and identified as a nonselective cation channel with six transmembrane domains that is structurally
. related to the TRP (transient receptor potential) channel family. Binding of capsaicin . . to VR1 allows sodium, calcium and possibly potassium ions to flow down their concentration gradients, causing initial depolarization and release of neuro- . transmitters from the nerve terminals. VRI can therefore be viewed as a molecular integrator of chemical and physical stimuli that elicit neuronal signals In a pathological conditions or diseases.
There are abundant of direct or indirect evidence that shows the relation between
VRI activity and diseases such as pain, ischaemia, and inflammatory (e.g., WO 99/00115 and 00/50387). Further, it has been demonstrated that VR1 transduce reflex signals that are involved in the overactive bladder of patients who have damaged or abnormal spinal reflex pathways [De Groat WC: A neurologic basis for the overactive bladder. Urology 50 (6A Suppl): 36-52, 1997]. Desensitisation of the afferent nerves by depleting neurotransmitters using VR agonists such as capsaicin has been shown to give promising results in the treatment of bladder dysfunction - associated with spinal cord injury and multiple sclerosis [(Maggi CA: Therapeutic potential of capsaicin-like molecules - Studies in animals and humans. Life Sciences 51: 1777-1781, 1992) and (DeRidder D; Chandiramani V; Dasgupta P; VanPoppel
H; Baert L; Fowler CJ: Intravesical capsaicin as a treatment for refractory detrusor hyperreflexia: A dual center study with long-term followup. J. Urol. 158: 2087- 2092, 1997)].
It is anticipated that antagonism of the VR1 receptor would lead to the blockage of neurotransmitter release. resulting in prophylaxis and treatment of the condition and diseases associated with VR1 activity. . It is therefore expected that antagonists of the VR1 receptor can be used for the prophylaxis and treatment of the condition and diseases including chronic pain, neuropathic pain, postoperative pain, rheumatoid arthritic pain, neuralgia, neuropa- thies, algesia, nerve injury, ischaemia, neurodegeneration, stroke, incontinence,
. inflammatory disorders such as asthma and COPD, urinary incontinence (UI) such as urge urinary incontinence (UUI), and/or overactive bladder.
WO 00/50387 discloses the compounds having a vanilloid agonist activity repre- , sented by the general formula:
RY
H o
REO * ~N" OCH, : Pp oo OR” } wherein; x* is an oxygen or sulfur atom;
A? is -NHCH,- or -CHz-;
R® is a substituted or unsubstituted C,.4 alkyl group, or R*'CO-; : wherein
R* is an alkyl group having 1 to 18 carbon atoms, an alkenyl group having 2 to 18 carbon atoms, or substituted or unsubstituted aryl group having 6 to 10 carbon atoms; a.
R® is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy : group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms or a halogen atom; :
RS is ahydrogen atom, an alkyl group having 1 to 4 carbon atom, an aminoalkyl, . a diacid monoester or a-alkyl acid; and . the asteric mark * indicates a chiral carbon atom, and their pharmaceutically acceptable salts. © WO 2000/61581 discloses amine derivatives represented by the general formula: ’ rR’ Rr"
NH
NH Hs
O N._ CH; O ogo nt
N CH, os S
N— wherein
R’.R”) represent (F, F), (CFs, H), or (iPr, iPr) as useful agents for diabetes, hyperlipemia, arteriosclerosis and cancer. : ‘ WO 00/75106 discloses the compounds represented by the general formula:
~ or xl
J
NH . 0
N-Z ’
RY
= NT o
TR
NGF wherein
Z represents 0
JQ
H,N—(CH,) 6 HN" (CH) = 0 rR
PY N
HN (CH,) w6—— or 257 hd i
OH 0 in which a: Ca . . . .wG
Ris hydrogen, Ci; alkyl. Cie cycloalkyl. or the like, end R7 1s amino-C..s alkyl, aminocarbonyl-C:.¢ aixyi, or 2vdroxyamino- carbony! C..s alkyvi: and 92 . : oo. . . ~ . Lo. I
R™ and R°" are independently selected for the group consisting of H.
C... av]. C.e alkyvlhio. Cie alkoxy. fluore, chloro. bromo, 13 iodo. anc nitre: ‘ as useful agents for treaung MMP-mediated diseases in manmals.
a. , X
Aro A AL
H H wherein :
Ar, is heterocycle;
An is tetrahydronapthy; and
L and Q are defined in this specification; as useful agents for treating inflammation, immune related disease, pain and diabetes.
However, none of these reference discloses simple hydroxy-tetrahydro-naphthalenyl- urea derivatives having VR1 antagonistic activity.
The development of a compound which has effective VR! antagonistic activity and can be used for the prophylaxis and treatment of diseases associated with VRI activity, in particular for the treatment of urinary incontinence, urge ummary —. incontinence, overactive bladder as well as pain, and/or inflammatory diseases such as asthma and COPD has been desired.

Claims (1)

  1. } | -87- Claims Co
    1. A hydroxy-tetrahydro-naphthalenylurea derivative of the formula (I), its ‘ tautomeric or stereoisomeric form, or a salt thereof:
    5 . 0 J X HNT NT H : HO Z' ey) 72 wherein ‘ X represents Cg alkyl, 10 1 R? rR R? Jf 7 , or in which 13 Y represents a direct bond, pa i il La a ) , or R* R°® R!, R? and R? independently represent hydrogen, halogen, hydroxy, nitro, carboxy, amino, Ci.s alkylamino, di(Cis alkyl)amino,
    Css cycloalkylamino, C;s alkoxycarbonyl, phenyl, benzyl, sulfonamide, C,.s alkanoyl, Ci. alkanoylamino, carbamoyl, . : Ci.¢ alkylcarbamoyl, cyano, C.¢ alkyl optionally substituted by cyano, Cy alkoxycarbonyl or-mono-, di-, or tri-halogen, C,.¢ ’ alkoxy optionally substituted by mono-, di-, or tri- halogen, phenoxy optionally substituted by halogen or C,.¢ alkyl, or Cy. : alkylthio optionally substituted by mono-, di-, or tri- halogen; RY, R35, R® and R’ independently represent hydrogen, C,. alkyl or phenyl; oo z! represents hydrogen or C,.¢ alkyl; and : A represents hydrogen, halogen or C;.¢ alkyl. | : C2 The hydroxy-tetrahydro-naphthalenylurea derivative of the formula (I), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 1, wherein ‘ X represents Co 1 R2 | Rr . ) : R? R3 Ny vy i. , or : : | : in which : 'Y represents a direct bond, or
    . RS * ~ RY, R? and R® independently represent hydrogen, halogen, hydroxy, | nitro, carboxyl, amino, Cj. alkylamino, di(C).¢ alkyl)amino, Css cycloalkylamino, C, alkoxycarbonyl, phenyl, benzyl, sulfonamide, Ci alkanoyl, Ci¢ alkanoylamino, carbamoyl,
    Ci.¢ alkylcarbamoyl, cyano, Cj alkyl optionally substituted by cyano, C; alkoxycarbonyl or mono-, di-, or tri-halogen, Ci - alkoxy optionally substituted by mono-, di-, or tri- halogen, phenoxy optionally substituted by halogen or Cy alkyl, or Cy. . alkylthio optionally substituted by mono-, di-, or tri- halogen; R* and R® independently represent hydrogen or Cig alkyl; and oo Z! and Z? each represent hydrogen. 3 The hydroxy-tetrahydro-naphthalenylurea derivauve of the formula (I), its rautomeric or stereoisomeric IOTm. Or a sait thereof as claimed in claim 1. wherein X represents oC
    1] . R2 \ rR . R? R3 RS , Or in which Y © represents a direct bond or RS - A R - R!, R? and R® independently represent hydrogen, halogen, di(C,¢ : : alkyl)amino, Cs. cycloalkylamino, Ci.¢ alkoxycarbonyl, Ci. B alkyl optionally substituted by cyano, C1. alkoxycarbonyl or mono-, di-, or tri-halogen, C,. alkoxy optionally substituted by mono-, di-, or tri- halogen, phenoxy optionally substituted, by halogen or Cy. alkyl, or Cy. alkylthio optionally substituted : Sa by mono-, di-, or tri- halogen; . oo oo Rand R’ each represent hydrogen; and~ oo no © Z'and 7? each represent hydrogen. Co
    - 4. The hydroxy-tetrahydro-naphthalenylurea derivative of the formula @), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 1, wherein X represents | oo 1 R2 } . | ; 2a Ny
    ~ in which . Y represents a direct bond or iy A R in which oo : R! and R? independently represent hydrogen, chloro, bromo, fluoro, cyclopentylamino, trifluoromethyl, or trifluoromethoxy; . oo rR? ,R% and R® each represent hydrogen; and Z' and 7? each represent hydrogen. : | | Co oo
    S. The hydroxy-tetrahydro-naphthalenylurea denivative of the formula M, its tautomeric or stereoisomeric form. or a salt thereof as claimed in claims 1, wherein : X represents mE r . R> ~~ =? in which : Y represents a direct bond or
    R° - in which R! and R? independently represent hydrogen, chloro, bromo, fluoro, cyclopentylamino, trifluoromethyl, or trifluoromethoxy; R?, R* and R® each represent hydrogen; and ] Z! and Z? each represent hydrogen. -
    6. A hydroxy-tetrahydro-naphthalenylurea derivative of the formula (I), its tautomeric or stereoilsomeric form, or a salt thereof as claimed in claim 1, wherein said hydroxy-tetrahydro-naphthalenylurea derivative of the formula
    15. | (I) 1s selected from the group consisting of: N-[4-chloro-3-(trifluoromethyl)phenyl}-N'-(7-hydroxy-5,6,7,8-tetrahydro-1- naphthalenyl)urea; | Co N-(3-chlorophenyl)-N'-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)urea; N-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)-N'-[3-(trifluoromethyl)- phenyl]urea; : N-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)-N'-[4-(trifluoromethyl)- phenyljurea; Ethyl 3-({[(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)amino]carbonyl} - amino)benzoate; - N-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)-N'-(1-naphthyl)urea; : N-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)-N'-(2-naphthyl)urea; N-(3,4-dichlorophenyl)-N'-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)- urea;
    N-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)-N'-(4-isopropylphenyljurea; ] oo N-(7-hydroxy-5,6,7,8-tetrahydro- 1-naphthalenyl)-N'-(4-phenoxyphenyl)urea; N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-(7-hydroxy-5,6,7,8-tetrahydro-1- . naphthalenyljurea;
    N-(7-hydroxy-5,6,7,8-tetrahydro- 1-naphthalenyl)-N'-phenylurea; oo N-(4-chlorophenyl)-N'-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)urea; N-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)-N'-[2-(trifluoromethyl)-
    phenyllurea; N-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)-N'-[4-(trifluoromethyl)- phenyljurea;. N-(3,4-dichlorophenyl)-N'-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)- urea; B . N-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)-N'-[4-(trifluoromethoxy)- phenyl]urea; | N-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)-N'-[4-(tr1 fluoromethoxy)- ‘benzyl]urea; Co N-(7-hydroxy-5,6,7,8-tetrahydro- 1-naphthalenyl)-N'-(2,4,6-trimethoxy- benzyl)urea; : | a N-(2,6-difluorobenzyl)-N'-(7-hydroxy-3,6,7.8-tetrahvdro- 1 -naphthalenyl)- urea; N-(7-hvdroxy-5,6,7.8-tewrahvdre- 1 -naphthalenv!)-N'-T 4-(irifluoromethv!)- benzyljurea, N-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)-N'-i 4-(trifluoromethoxy)- benzyllurea; : . oo N-[2-(4-chlorophenyl)ethyl]-N'-(7-hydroxy-5,6,7,8-tetrahydro- 1- naphthalenyl)urea; and N-[3-fluoro-4-(trifluoromethyl)benzyl]-N'-(7-hydroxy-5,6,7,8-tetrahydro-1- naphthalenyl)urea.
    7. A hydroxy-tetrahydro-naphthalenylurea derivative of thse formula {@, . wherein said Bydroxy-tetrahydro-naphthalenylurea derivative of the formula (I) 1s selected from the group consisting of: ’ N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-[(7S)-7-hydroxy-5,6,7,8-tetra- hydro-1-naphthalenyl]urea; N-[4-chloro-3-(trifluoromethyl)phenyl}-N'-[(7R)-7-hydroky-5,6,7,8-tetra- hydro-1-naphthalenylJurea; oo N-[(7R)-7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl]-N'-[4-(trifluoro- methyl)benzyljurea; N-[(78)-7-hydroxy-5,6,7,8-tetrahydro- 1-naphthalenyl]-N'-[4-(trifluoro- : methyl)benzyl)urea; . N-[(7R)-7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl]-N'-[4~(trifluoro- methoxy)benzyl]urea; and . ) B - N-[(7S)-7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl}-N-[4-(trifluoro- methoxy)benzy]urea. | Co 8 A medicament comprising hydroxy-tetrahydro-naphthalenylurea denivative of . 20 the formula (I), its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof as claimed in claim 1 as an active ingredient.
    -9. The medicament as claimed. in claim 8, further comprising one or more pharmaceutically acceptable excipients.
    10. The medicament as claimed in claim 8, wherein said hydroxy-tetrahydro- naphthalenylurea derivative of the formula @, its tautomeric or stereo- ’ isomeric form, or a physiologically acceptable salt thereof is a VRI antagonist.
    oo oo -95-
    11. The medicament as claimed in claim 8 for the treatment and/or prevention of an urological disorder or disease. : [l ) ) . 12. The medicament as claimed in claim 11, wherein said urological disorder or disease is urge urinary incontinence or overactive bladder.
    13. The medicament as claimed in claim 8 for the treatment and/or prevention of pain.
    14. The medicament as claimed in claim 13, wherein said pain is chronic pain, oo neuropathic pain, postoperative pain, or rheumatoid arthritic pain.
    15. The medicament as claimed in claim 8 for the treatment and/or prevention of a disorder or disease related to pain. SE :
    16. The medicament as claimed mn claim 15, wherein said disorder or disease ~ related to pain is neuralgia, neuropathies, algesia, nerve injury, ischaemia, neurodegeneration, or stroke.
    17. The medicament as claimed in claim § for the treatment and/or prevention of ar inflammatory disorder or disease.
    18. The medicament as claimed in claim 17. wherein said inflammatory disorder or disease 1s asthma or COPD.
    16. Use of compounds according to claim 1 for manufacturing a medicament for . | the treatment and/or prevention of an urological disorder or disease. ’ 20. Use of compounds according to claim 1 for manufacturing a medicament for the treatment and/or prevention of pain. :
    21. Use of compounds according to claim 1 for manufacturing a medicament for the treatment and/or prevention of an inflammatory disorder or disease. .
    22. Process for controlling an urological disorder or disease in humans and )
    5. . amimals by administration of a VR1-antagonisticly effective amount of at least one compound according to claim 1.
    23. Process for controlling pain in humans and animals by administration of a VR1-antagonisticly effective amount of at least one compound according to claim 1. oo
    24. Process for controlling an inflammatory disorder or disease in humans and animals by administration of a VR1-antagonisticly effective amount of at least one compound according to claim I. : To EE
ZA2004/08993A 2002-05-08 2004-11-05 Hydroxy tetrahydro naphthalenylurea derivatives ZA200408993B (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GBGB0210512.0A GB0210512D0 (en) 2002-05-08 2002-05-08 Tetrahydro-napthalene derivatives
GBGB0227262.3A GB0227262D0 (en) 2002-05-08 2002-11-21 Tetrahydro-naphthalene derivatives
PCT/EP2003/004395 WO2003095420A1 (en) 2002-05-08 2003-04-28 Hydroxy tetrahydro-naphthalenylurea derivatives

Publications (1)

Publication Number Publication Date
ZA200408993B true ZA200408993B (en) 2006-01-25

Family

ID=9936269

Family Applications (1)

Application Number Title Priority Date Filing Date
ZA2004/08993A ZA200408993B (en) 2002-05-08 2004-11-05 Hydroxy tetrahydro naphthalenylurea derivatives

Country Status (13)

Country Link
KR (1) KR101000688B1 (en)
AR (1) AR039983A1 (en)
CU (1) CU23422B7 (en)
DO (1) DOP2003000642A (en)
EC (1) ECSP045413A (en)
GB (2) GB0210512D0 (en)
GT (1) GT200300102A (en)
MA (1) MA30728B1 (en)
MY (1) MY155011A (en)
PE (1) PE20040363A1 (en)
PT (1) PT1506167E (en)
UA (1) UA77301C2 (en)
ZA (1) ZA200408993B (en)

Also Published As

Publication number Publication date
AR039983A1 (en) 2005-03-09
MA30728B1 (en) 2009-10-01
KR20040108784A (en) 2004-12-24
PE20040363A1 (en) 2004-07-03
DOP2003000642A (en) 2003-11-15
CU23422B7 (en) 2009-09-08
ECSP045413A (en) 2005-01-03
GB0210512D0 (en) 2002-06-19
PT1506167E (en) 2007-12-10
UA77301C2 (en) 2006-11-15
GT200300102A (en) 2004-03-17
MY155011A (en) 2015-08-28
KR101000688B1 (en) 2010-12-10
GB0227262D0 (en) 2002-12-31

Similar Documents

Publication Publication Date Title
JP7057317B2 (en) Dual mechanism inhibitor for the treatment of disease
JP5980846B2 (en) Beta- and gamma-amino-isoquinolinamide compounds and substituted benzamide compounds
KR101310882B1 (en) Alpha-aminoamide derivatives useful in the treatment of lower urinary tract disorders
TWI453013B (en) Use of n-(2,4-dimethyl-6-morpholin-4-yl-pyridin-3-yl)-3,3-dimethyl-butyramide and medicament comprising said compound
KR20050088295A (en) Pharmaceutical composition comprising a beta-3-adrenoceptor agonist and a serotonin and/or norepinephrine reuptake inhibitor
US9464066B2 (en) Deuterated compounds useful for treating neurodegenerative diseases
KR20060010717A (en) New arylpiperazinyl compounds
US20080280954A1 (en) Method of Improving Wakefulness
US20220354839A1 (en) Piperidine urea derivatives as soluble epoxide hydrolase inhibitors
JP2007509896A (en) Pharmaceutical composition containing β-3-adrenoceptor agonist and α antagonist and / or 5-α reductase inhibitor
JP5571072B2 (en) How to treat alpha-adrenergic mediated symptoms
JP5042625B2 (en) Α-Aminoamide derivatives useful as anti-inflammatory agents
WO2017129061A1 (en) Application of substituted cinnamamide derivatives in preparation of anti-anxiety medications
US9603845B2 (en) Prophylactic agent and/or therapeutic agent for stress urinary incontinence
ZA200408993B (en) Hydroxy tetrahydro naphthalenylurea derivatives
WO2005084675A1 (en) Kv1.5-blocker for the selective increase of atrial contractility and treatment of cardiac insufficiency
US7470708B2 (en) Acidic quinoline derivatives and their use for the prevention and/or treatment of hyperglycaemia-related pathologies
KR101708764B1 (en) Pharmaceutical composition for treating or preventing central nervous system disease
JP2007509897A (en) Pharmaceutical composition comprising β-3-adrenoceptor agonist and α-agonist
JP2008532956A (en) Use of hydroxytetrahydro-naphthalene derivatives
JP2003505414A (en) Azetidine compounds in CNA and eye diseases
JP2003505418A (en) Azetidine carboxamide derivatives for the treatment of CNS disorders
DE60029985T2 (en) USE OF NEUROPHILIN LIGANDS FOR THE TREATMENT OF EYE DISEASES
WO2010047295A1 (en) Medicine for preventing or treating pain related to herpes zoster