Israel state records י"ג בשבט התשס"ח January 20, 2008

אנלוגים מקרו–מעגליים של הליקונדרין B, שיטות לשימוש בהם ומספר תוצרי–ביניים להכנתם	MACROCYCLIC HALICHONDRIN B ANALOGS, METHODS OF THEIR USE AND SOME INTERMEDIATES FOR THEIR PREPARATION
[54]
	16.06.1999					[22]
	US	[33]	17.06.1998	[32]	60/089682	[31]
Int. Cl.8 A61K 009/00, 047/34, 047/42, A61P 035/00, C07D 405/14, 493/04, 493/22, C07K 002/00, G01N 033/15, 033/53						[51]
			EISAI CO.,LTD., JAPAN			[71]
	WO/1999/065894					[87]
זליגסון גבריאלי ושות', רח' יבנה 31 , ת.ד. 1426, תל אביב			SELIGSOHN GABRIELI & CO., 31 YAVNE ST., P.O.B. 1426, TEL AVIV 61013			[74]

[57] A compound of the formula:


wherein A is a C_1-6 saturated or C_2-6 unsaturated hydrocarbon skeleton, said skeleton being unsubstituted or having between 1 and 10 substituents, inclusive, independently selected from cyano, halo, azido, oxo, and Q₁; each Q₁ is independently selected from OR₁, SR₁, SO₂R₁, OSO₂R₁, NR₂R₁, NR₂(CO)R₁, NR₂(CO)(CO)R₁, NR₄(CO)NR₂R₁, NR₂(CO)OR₁, (CO)OR₁, O(CO)R₁, (CO)NR₂R₁, and O(CO)NR₂R₁;

each of R₁, R₂, R₄, R₅, and R₆ is independently selected from H, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_6-10 aryl, C_6-10 haloaryl, C_6-10 hydroxyaryl, C_1-3 alkoxy-C₆ aryl, C₆ aryl, C_6-10 aryl-C_1-6 alkyl-C_6-10 aryl, C_6-10 haloaryl-C_1-6 alkyl, C_1-6 alkyl-C_6-10 haloaryl, (C_1-3 alkoxy-C₆ aryl)-C_1-3 alkyl, C_2-9 heterocyclic radical, C_2-9 heterocyclic radical-C_1-6 alkyl, C_2-9 heteroaryl, and C_2-9 heteroaryl-C_1-6 alkyl;

each of D and D' is independently selected from R₃ and OR₃, wherein R₃ is H, C_1-3 alkyl, or C_1-3 haloalkyl;

n is 0 or 1;

E is R₅ or OR₅;

G is O, S, CH₂, or NR₆;

each of J and J' is independently H, C_1-6 alkoxy, or C_1-6 alkyl; or J and J' taken together are =CH₂ or –O-(straight or branched C_1-5 alkylene)-O-;

Q is C_1-3 alkyl;

T is ethylene or ethenylene, optionally substituted with (CO)OR₇, where R₇ is H or C_1-6 alkyl;

each of U and U is independently H, C_1-6 alkoxy, or C_1-6 alkyl; or U and U' taken together are =CH₂ or –O-(straight or branched C_1-5 alkylene)-O-; X is H or C_1-6 alkoxy; each of Y and Y' is independently H or C_1-6 alkoxy; or Y and Y' taken together are =O =CH₂ or –O-(straight or branched C_1-5 alkylene)-O-; and each of Z and Z' is independently H or C_1-6 alkoxy; or Z and Z' taken together are =O =CH₂, or –O- (straight or branched C_1-5 alkylene)-O-; provided that there are no incompatibilities between substituents, or a pharmaceutically acceptable salt thereof.

Also claimed as novel are compounds of the formulae

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140554			[21][11]
תולדות אוקסאמיל ותכשירי רוקחות המכילים אותן			OXAMYL DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME			[54]
	01.07.1999					[22]
	US	[33]	02.07.1998	[32]	60/091689	[31]
	US		22.10.1998		09/177549
Int. Cl.7 A61K 031/16, 031/33, A61P 043/00, C07C 237/22, 317/50, C07D 211/60, 239/34, 261/18, 309/30, 311/32						[51]
			IDUN PHARMACEUTICALS, INC., U.S.A.			[71]
	WO/2000/001666					[87]
וולף, ברגמן וגולר, רחוב קרן היסוד 19ב' , ת.ד. 1352, ירושלים			WOLFF, BREGMAN AND GOLLER, 19B KEREN HAYESOD ST., P.O.B. 1352, JERUSALEM 91013			[74]

[57] A compound of the following formula:


wherein:

A is a natural or unnatural amino acid of the formulae

B is hydrogen atom, a deuterium atom, alkyl, cycloalkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, 2-benzoxazolyl, substituted 2-oxazolyl, (CH₂)_n cycloalkyl, (CH₂)_n phenyl, (CH₂)_n(substituted phenyl), (CH₂)_n(1 or 2-naphthyl), (CH₂)_n (substituted 1 or 2-naphthyl), (CH₂)_n(heteroaryl), (CH₂)_n (substituted heteroaryl), halomethyl, CO₂R¹², CONR¹³R¹⁴, CH₂ZR¹⁵, CH₂OCO(aryl), CH₂OCO(heteroaryl), or CH₂OPO(R¹⁶)R¹⁷, where Z is an oxygen or a sulfur atom, or B is a group of the formulae

R¹ is alkyl, cycloalkyl, (cycloalkyl) alkyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, naphthyl, substituted naphthyl, (1 or 2 naphthyl) alkyl, heteroaryl, substituted heteroaryl, (heteroaryl) alkyl, substituted (heteroaryl) alkyl, R^1a(R^1b)N, or R^1cO; and

R² is hydrogen, C_1-6 alkyl, cycloalkyl, (cycloalkyl) alkyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, naphthyl, substituted naphthyl, (1 or 2 naphthyl) alkyl, or substituted (1 or 2 naphthyl) alkyl;

and wherein:

R^1a and R^1b are independently hydrogen, alkyl, cycloalkyl, (cycloalkyl) alkyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, naphthyl, substituted naphthyl, (1 or 2 naphthyl) alkyl, substituted (1 or 2 naphthyl) alkyl, heteroaryl, substituted heteroaryl, (heteroaryl) alkyl or substituted (heteroaryl) alkyl, with the proviso that R^1a and R^1b cannot both be hydrogen;

R^1c is alkyl, cycloalkyl, (cycloalkyl) alkyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, naphthyl, substituted naphthyl, (1 or 2 naphthyl) alkyl, substituted (1 or 2 naphthyl) alkyl, heteroaryl, substituted heteroaryl, (heteroaryl) alkyl, or substituted (heteroaryl) alkyl;

R³ is C_1-6 alkyl, cycloalkyl, phenyl, substituted phenyl, (CH₂)_nNH₂, (CH₂)_nNHCOR⁹, (CH₂)_nN(C=NH)NH₂, (CH₂)_mCO₂R², (CH₂)_mOR¹⁰, (CH₂)_mSR¹¹, (CH₂)_ncycloalkyl, (CH₂)_nphenyl, (CH₂)_n (substituted phenyl), (CH₂)_n(1 or 2-naphthyl) or (CH₂)_n(heteroaryl), wherein heteroaryl includes pyridyl, thienyl, furyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, pyrazinyl, pyrimidinyl, triazinyl, tetrazolyl, and indolyl;

R^3a is hydrogen or methyl, or R³ and R^3a taken together are – (CH₂)_a- where d is an integer from 2 to 6;

R⁴ is phenyl, substituted phenyl, (CH₂)_mphenyl, (CH₂)_m(substituted phenyl), cycloalkyl, or benzofused cycloalkyl;

R⁵ is hydrogen, C_1-6 alkyl, cycloalkyl, phenyl, substituted phenyl, (CH₂)_n cycloalkyl, (CH₂)_n phenyl, (CH₂)_n (substituted phenyl), or (CH₂)_n(1 or 2-naphthyl);

R⁶ is hydrogen, fluorine, oxo, C_1-6 alkyl, cycloakyl, phenyl, substituted phenyl, naphthyl, (CH₂)_ncycloalkyl, (CH₂)_n phenyl, (CH₂)_n (substituted phenyl), (CH₂)_n(1 or 2-naphthyl), OR¹⁰, SR¹¹ or NHCOR⁹;

R⁷ is hydrogen, oxo, C_1-6 alkyl, cycloalkyl, phenyl, substituted phenyl, naphthyl, (CH₂)_ncycloalkyl, (CH₂)_nphenyl, (CH₂)_n(substituted phenyl), or (CH₂)_n(1 or 2-naphthyl);

R⁸ is C_1-6 alkyl, cycloalkyl, (CH₂)_n cycloalkyl, (CH₂)_nphenyl, (CH₂)_n(substituted phenyl), (CH₂)_n(1 or 2-naphthyl), or COR⁹;

R⁹ is hydrogen, C_1-6 alkyl, cycloalkyl, phenyl, substituted phenyl, naphthyl, (CH₂) cycloalkyl, (CH₂) phenyl, (CH₂)_n(substituted phenyl), (CH₂)_n(1 or 2-naphthyl), OR¹², or NR¹³R¹⁴;

R¹⁰ is hydrogen, C_1-6 alkyl, cycloalkyl, phenyl, substituted phenyl, naphthyl, (CH₂) cycloalkyl, (CH₂)_n (substituted phenyl), or (CH₂)_n (1 or 2-naphthyl);

R¹¹ is C_1-6 alkyl, cycloalkyl, phenyl, substituted phenyl, naphthyl, (CH₂)_ncycloalkyl, (CH₂)_n phenyl, (CH₂)_n(substituted phenyl), or (CH₂)_n (1 or 2-naphthyl);

R¹² is C_1-6 alkyl, cycloalkyl, (CH₂)_ncycloalkyl, (CH₂)_nphenyl, (CH₂)_n(substituted phenyl), or (CH₂)_n(1 or 2-naphthyl);

R¹³ is hydrogen, C_1-6 alkyl, cycloalkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, (CH₂)_ncycloalkyl, (CH₂)_n phenyl, (CH₂)_n(substituted phenyl), or (CH₂)_n(1 or 2-naphthyl); R¹⁴ is hydrogen or C_1-6 alkyl;

or R¹³ and R¹⁴ taken together form a five to seven membered carbocyclic or heterocyclic ring, such as morpholine, or N-substituted piperazine;

R¹⁵ is phenyl, substituted phenyl, naphthyl, substituted naphthyl, heteroaryl, (CH₂)_nphenyl, (CH₂)_n(substituted phenyl), (CH₂)_n(1 or 2-naphthyl), or (CH₂)_n(heteroaryl);

R¹⁶ and R¹⁷ are independently C_1-6 alkyl, cycloalkyl, phenyl, substituted phenyl, naphthyl, phenylalkyl, substituted phenylalkyl, or (cycloalkyl) alkyl;

R¹⁸ and R¹⁹ are independently hydrogen, alkyl, phenyl, substituted phenyl, (CH₂)_nphenyl, (CH₂)_n (substituted phenyl), or R¹⁸ and R¹⁹ taken together are –(CH=CH)₂-;

R²⁰ is hydrogen, alkyl, phenyl, substituted phenyl, (CH₂)_nphenyl, (CH₂)_n(substituted phenyl);

R²¹, R²² and R²³ are independently hydrogen, or alkyl;

X is CH₂,(CH₂)₂, (CH₂)₃, or S;

Y¹ is O or NR²³;

Y² is CH₂, O, or NR²³;

a is 0 or 1 and b is 1 or 2, provided that when a is 1 then b is 1;

c is 1 or 2, provided that when c is 1 then a is 0 and b is 1;

m is 1 or 2; and

n is 1, 2, 3 or 4;

or a pharmaceutically acceptable salt thereof.

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140803			[21][11]
שימוש ב (–) – ציס – 6 –פניל – 5 – [4 – (2 – פירולידין – 1 – אתוקסי) – פניל] – 8,7,6,5 – טטראהידרו – נפתלן – 2 אול בהכנת תרופה לטיפול בזירמה מקדמת			USE OF (-)- CIS - 6 - PHENYL - 5 - [4 - (2 - PYRROLIDIN - 1 - YL - ETHOXY) - PHENYL] - 5, 6, 7, 8 - TETRAHYDRO - NAPHTHALENE - 2 - OL IN THE PREPARATION OF A MEDICAMENT FOR TREATING PREMATURE EJACULATION			[54]
	08.01.2001					[22]
	US	[33]	12.01.2000	[32]	60/175704	[31]
Int. Cl.8 A61K 031/40, 045/00, 045/06, A61P 015/10, 015/12						[51]
			PFIZER PRODUCTS, INC., U.S.A.			[71]
לוצאטו את לוצאטו, גן תעשייה, עומר , ת.ד. 5352, באר שבע			LUZZATTO & LUZZATTO, INDUSTRIAL PARK, OMER, P.O.B. 5352, BEER-SHEVA 84152			[74]

[57] Use of an effective amount of (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol, or a nontoxic pharmaceutically acceptable acid addition salt, N-oxide, ester quaternary ammonium salt or prodrug thereof, in the preparation of a medicament for treating premature ejaculation in a male.

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142408			[21][11]